Substituted pyridine and pyrazine compounds as pde4 inhibitors

ABSTRACT

The invention provides a chemical entity of Formula (I), and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating treating peripheral disorders, including inflammatory and renal disorders.

RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application is a continuation of U.S. patentapplication Ser. No. 16/001,883, filed on Jun. 6, 2018, which is acontinuation of U.S. patent application Ser. No. 14/770,759, filed onAug. 26, 2015, which is the U.S. National Phase of InternationalApplication No. PCT/US2014/021426, filed on Mar. 6, 2014, which claimspriority to and the benefit of U.S. Application No. 61/786,288, filed onMar. 14, 2013, the disclosure of which is incorporated herein in itsentirety by reference.

BACKGROUND Field

The present invention relates to certain substituted pyridine andpyrazine compounds as inhibitors of PDE4 enzymes; derivatives of suchcompounds; compositions of such compounds; methods of making them; andtheir use in various methods, including detection and imagingtechniques; enhancing neuronal plasticity; treating neurologicaldisorders, including psychiatric, neurodegenerative, cerebrovascular,cognitive and motor disorders; providing neuroprotection; enhancing theefficiency of cognitive and motor training; facilitating neurorecoveryand neurorehabilitation; and treating peripheral disorders, includinginflammatory and renal disorders.

Description of the Related Technology

The mammalian phosphodiesterases (PDEs) are a group of closely relatedenzymes divided into 11 families (PDE1-11) based on substratespecificity, inhibitor sensitivity and more recently, on sequencehomology. The 11 families are coded by 21 genes, providing several ofthe families with multiple members. All mammalian PDEs share a conservedcatalytic domain located in the COOH-terminal portion of the protein. InGAF-containing PDEs, one or both GAFs can provide dimerization contacts.In addition, one of the GAFs in each of these proteins provides forallosteric cGMP binding (PDE2, PDE5, PDE6, PDE11), allosteric cAMPbinding (PDE10), and regulation of catalytic site functions (PDE2, PDE5,PDE6). The other families of PDEs have unique complements of varioussubdomains (UCR, NHR, PAS, membrane association) that contribute toregulation of activity. PDEs 1, 2, 3, and 4 are expressed in manytissues, whereas others are more restricted. In most cells, PDE3 andPDE4 provide the major portion of cAMP-hydrolyzing activity (Francis,Physiological Reviews, 2011, 91, 651-690).

The PDE4 family includes four isoforms (PDE4A, B, C and D) with morethan 20 splice variants, making it one of the largest PDE subfamilies(Bender and Beavo, 2006). PDE4 enzymes hydrolyze cAMP with a substrateapparent Km of 1-5 uM for cAMP. The PDE4 enzyme is reported to beregulated by two upper control region (UCR) domains. Depending ondifferential RNA splicing, PDE4 variants can be distinguished into twomajor subgroups: long and short forms (Conti et al., J Biol Chem., 2003,278, 5493-5496). Nine splice variants have been reported. PDE4D1, 4D2and 4D6 all are shorter forms lacking UCRs. PDE4D3, 4D4, 4D5, 4D7, 4D8and 4D9 are longer forms that contain both UCRs and N-terminal domainsimportant for their subcellular localization (Bender and Beavo, 2006).Long form PDE4D3 activity is increased by PKA phosphorylation via Ser54in the N-terminal UCR1 (Alvarez et al., Mol Pharmacol., 1995, 48,616-622; Sette et al., J Biol Chem., 1996, 271, 16526-16534).Conversely, Erk2 phosphorylation of Ser597 in the C-terminus of PDE4D3causes a reduction in catalytic activity. One or several PDE4D isoformsare expressed throughout most tissues tested, including cortex,hippocampus, cerebellum, heart, liver, kidney, lung and testis (Richteret al., Biochem. J., 2005, 388, 803-811). The localization andregulation of PDE4D isoforms is thought to allow for tight and localregulation of cAMP levels, possibly limiting signal propagation inspecific subcellular compartments.

Numerous studies have highlighted a role for PDEs generally, and PDE4 inparticular, in modulating intracellular signaling pathways that regulatemany physiological processes, including those underling neuralplasticity, cognition, and memory. In particular, PDEs play an importantrole in intracellular signal transduction pathways involving the secondmessengers, cAMP and cGMP. These cyclic nucleotides function asubiquitous intracellular signaling molecules in all mammalian cells. PDEenzymes hydrolyze cAMP and cGMP by breaking phosphodiester bonds to formthe corresponding monophosphates (Bender and Beavo, Pharmacol. Rev.,2006, 58 (3), 488-520). PDE activities are modulated in coordinationwith adenylyl cyclase (AC) and guanylyl cyclase (GC) activities throughdirect effectors and feedback pathways, thereby maintaining cAMP andcGMP levels within optimum ranges for responsiveness to signals. Theability of extracellular signals to modulate the intracellularconcentration of cyclic nucleotides allows cells to respond to externalstimuli across the boundary of the cell membrane.

The cyclic nucleotide signaling cascades have been adapted to respond toa host of transduction systems including G-protein coupled receptors(GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotidestransmit their signal in the cell through a variety of tertiaryelements. The best described of these are cAMP dependent protein kinase(PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclicnucleotide to each enzyme enables the phosphorylation of downstreamenzymes and proteins functioning as effectors or additional elements inthe signaling cascade. Of particular importance to memory formation iscAMP activation of PKA, which phosphorylates cAMP responseelement-binding protein (CREB). pCREB is an activated transcriptionfactor, which binds to specific DNA loci and initiates transcription ofmultiple genes involved in neuronal plasticity. Both in vitro and invivo studies have associated alterations in cyclic nucleotideconcentrations with biochemical and physiological process linked tocognitive function (Kelly and Brandon, Progress in Brain Research, 2009,179, 67-73; Schmidt, Current Topics in Medicinal Chemistry, 2010, 10,222-230). Signal intensity and the levels of coincident activity at asynapse are established variables that can result in potentiation oftransmission at a particular synapse. Long term potentiation (LTP) isthe best described of these processes and is known to be modulated byboth the cAMP and cGMP signaling cascades.

Focus on the role of PDE4 in memory stems from the discovery of thePDE4-like Drosophila learning mutant dunce (dnc gene), a cyclicnucleotide phosphodiesterase of the PDE4 subtype (Yun and Davis, NucleicAcids Research, 1989, 17(20), 8313-8326). The dnc mutant flies aredefective in acquisition and/or short-term memory when tested in severaldifferent olfactory associative learning situations, with negative(Dudai et al., Proc Natl Acad Sci., 1976, 73(5), 1684-1688; Dudai Y.,Proc Natl Acad Sci., 1983, 80(17), 5445-5448; Tully and Quinn, Journalof Comparative Physiology, 1985, 157(2), 263-77) or positivereinforcement (Tempel et al., Proc Natl Acad Sci., 1983, 80(5),1482-1486). In mammals, PDE4D knockout animals display decreasedimmobility in the antidepressant tail-suspension and forced swim testmodels (Zhang et al., Neuropsychopharmacology, 2002, 27(4), 587-595),enhanced in vitro LTP in hippocampal CAI slices (Rutten et al., Eur. J.Neurosci., 2008, 28(3), 625-632), and enhanced memory in radial maze,object recognition, and Morris water maze tasks (Li et al., J.Neurosci., 2011, 31, 172-183).

Such observations highlight the interest in PDE-inhibition, includingPDE4-inhibition, as a therapeutic target for numerous disorders and incognitive enhancement. For example, by increasing cAMP levels, suchinhibitors may be useful in treating cognitive deterioration inneurodegenerative disorders such Parkinson's Disease and Alzheimer'sDisease, as well as generally improving cognition in normal, diseased,and aging subjects. Various small-molecule PDE4 enzyme inhibitors havebeen reported e.g., Aza-bridged bicycles (DeCODE Genetics; Intl. Pat.Appl. Publ. WO 2010/059836, May 27, 2010); N-substituted anilines(Memory Pharmaceuticals Corporation; Intl. Pat. Appl. Publ. WO2010/003084, Jan. 7, 2010); Biaryls (DeCODE Genetics; Intl. Pat. Appl.Publ. WO 2009/067600, May 28, 2009, WO 2009/067621, May 28, 2009);Benzothiazoles and benzoxazoles (DeCODE Genetics; U.S. Pat. Appl. Publ.US 2009/0130076, May 21, 2009); Catechols (DeCODE Genetics; U.S. Pat.Appl. Publ. US 2009/0131530, May 21, 2009), Pteridines (BoehringerIngelheim International G.m.b.H.; U.S. Pat. No. 7,674,788, Nov. 29,2007); Heteroaryl pyrazoles (Memory Pharmaceuticals Corporation; Intl.Pat. Appl. Publ. WO 2007/123953, Nov. 1, 2007); Naphthyridines (GlaxoGroup Limited; Intl. Pat. Appl. Publ. WO 2006/053784, May 26, 2006);Piperazinyldihydrothienopyrimidines (Boehringer Ingelheim InternationalG.m.b.H.; EP Pat. 1,874,781, Jun. 24, 2009); Nicotinamide derivatives(Pfizer, U.S. Pat. Appl. Publ. US 2005/0020587, Jan. 27, 2005);Heteroarylmethyl phenyl amines (Memory Pharmaceuticals Corporation; U.S.Pat. No. 7,087,625, Aug. 8, 2006); Naphthyridines (Novartis AG; EP Pat.1,443,925, Dec. 26, 2007; U.S. Pat. No. 7,468,370, Dec. 23, 2008).

However, PDE4 inhibitors have generally been associated with numerousside effects—most notably emesis—that have typically limited theirusefulness and tolerability (e.g., Giembycz, Curr. Opin. Pharm. 2005, 5,238-244). It is therefore desirable to develop improved PDE4 inhibitorssuch as those showing higher potency, greater specificity, and betterside effect profiles. The present invention meets these and other needsin the art by disclosing substituted pyridine and pyrazine compounds aspotent and well-tolerated PDE4 inhibitors.

SUMMARY

The invention provides a chemical entity of Formula (I):

whereinR¹, R², R³, R⁴, Y and Z have any of the values described herein.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

Chemical entities of compounds of Formula (I) are useful in wide rangeof methods as described herein. Isotopically-labeled compounds andprodrugs can be used in metabolic and reaction kinetic studies,detection and imaging techniques, and radioactive treatments. Thechemical embodiments of the present invention can be used to inhibitPDE4, in particular; to treat a disorder mediated by PDE4, inparticular, to enhance neuronal plasticity; to treat neurologicaldisorders, including neurodegenerative disorders, cognitive disorders,and cognitive deficits associated with CNS disorders; to conferneuroprotection; and to treat peripheral disorders, includinginflammatory and renal disorders. The chemical embodiments of thepresent invention are are also useful as augmenting agents to enhancethe efficiency of cognitive and motor training, in strokerehabilitation, to facilitate neurorecovery and neurorehabilitation, andto increase the efficiency of non-human animal training protocols. Theinvention is further directed to the general and specific embodimentsdefined, respectively, by the independent and dependent claims appendedhereto, which are incorporated by reference herein.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art to the present invention.

Abbreviations

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

Abbreviation Meaning ACN Acetonitrile AcOH Acetic Acid AIBN2,2′-Azobis(2-methylpropionitrile) BOC tert-Butyl dicarbonate n-BuLin-Butyl lithium DCM Dichloromethane Deoxo-Fluor ®Bis(2-methoxyethyl)aminosulfur trifluoride Dess-Martin Reagent ®1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one DIPEA,Hünig's base N,N-Ethyl-diisopropylamine or N,N-Diisopropyl-ethyl amineDMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSODimethylsulfoxide dppf 1,1′-Bis(diphenylphosphino)ferrocene EtOAc, or EAEthyl Acetate EtOH Ethanol HOAc or AcOH Acetic Acid HPLCHigh-performance liquid chromatography LAH Lithium aluminum hydrideLCMS, LC/MS Liquid chromatography-mass spectrometry MeOH Methanol NBSn-Bromosuccinimide, PdCl₂(dppf)-DCM adduct[1′1′-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloridedichloromethane adduct Pd(PPh₃)₄Tetrakis[triphenylphosphine]palladium(0) TBAF Tetrabutylammoniumfluoride TEA, Et₃N Triethylamine TFA Trifluoroacetic acid THFTetrahydrofuran TLC Thin layer chromatography XtalFluor ®(Diethylamino)difluorosulfonium tetrafluoroborate

Terms and Definitions

The use of subheadings such as “General,” “Chemistry,” “Compositions,”“Formulations,” etc., in this section, as well as in other sections ofthis application, are solely for convenience of reference and notintended to be limiting.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value.Alternatively, with respect to biological systems or processes, the term“about” can mean within an order of magnitude, within 5 fold, or within2 fold on either side of a value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation of such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity for which that could be obtained under the particularstoichiometric conditions. Concentrations that are given as percentagesrefer to mass ratios, unless indicated differently.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

A group of items linked with the conjunction “and” should not be read asrequiring that each and every one of those items be present in thegrouping, but rather should be read as “and/or” unless expressly statedotherwise. Similarly, a group of items linked with the conjunction “or”should not be read as requiring mutual exclusivity among that group, butrather should also be read as “and/or” unless expressly statedotherwise. Furthermore, although items, elements or components of theinvention may be described or claimed in the singular, the plural iscontemplated to be within the scope thereof unless limitation to thesingular is explicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended as opposed to limiting. As examples of theforegoing: the term “example” is used to provide exemplary instances ofthe item in discussion, not an exhaustive or limiting list thereof;adjectives such as “conventional,” “traditional,” “normal,” “criterion,”“known,” and terms of similar meaning should not be construed aslimiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or criterion technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to,” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. As will becomeapparent to one of ordinary skill in the art after reading thisdocument, the illustrated embodiments and their various alternatives maybe implemented without confinement to the illustrated examples.

Chemistry

The term “alkyl” refers to a fully saturated aliphatic hydrocarbongroup. The alkyl moiety may be a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “

”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples. Alkyl groups may be optionally substituted with oneor more substituents including, but not limited to, hydroxyl, alkoxy,cyano, thioalkoxy, amino, and aminoalkyl.

The term “haloalkyl” refers to the alkyl moiety, which may be astraight- or branched-chain alkyl group having from 1 to 12 carbon atomsin the chain substituted with a halo group. Examples of haloalkyl groupsinclude, but are not limited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂,—CH₂CH₂F, —CH₂CH₂Cl, or —CH₂CF₂CF₃.

The term “cyano” refers to the group —CN.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkylgroups listed or illustrated above are not exhaustive, and thatadditional species within the scope of these defined terms may also beselected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur) and N (nitrogen).

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Formulas

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

The symbols

and

are used as meaning the same spacial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spacial arrangement in chemical structuresshown herein.

Compounds

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound; and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R—COOH, encompassesreference to any one of, for example, R—COOH(s), R—COOH(sol), andR—COO-(sol). In this example, R—COOH(s) refers to the solid compound, asit could be for example in a tablet or some other solid pharmaceuticalcomposition or preparation; R—COOH(sol) refers to the undissociated formof the compound in a solvent; and R—COO-(sol) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO— upon dissociation in the medium being considered.

As used herein, the term “chemical entity” collectively refers to acompound, along with the derivatives of the compound, including salts,chelates, solvates, conformers, non-covalent complexes, metabolites, andprodrugs.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

In another example, an expression such as “exposing an entity to acompound of formula R—COOH” refers to the exposure of such entity to theform, or forms, of the compound R—COOH that exists, or exist, in themedium in which such exposure takes place. In still another example, anexpression such as “reacting an entity with a compound of formulaR—COOH” refers to the reacting of (a) such entity in the chemicallyrelevant form, or forms, of such entity that exists, or exist, in themedium in which such reacting takes place, with (b) the chemicallyrelevant form, or forms, of the compound R—COOH that exists, or exist,in the medium in which such reacting takes place. In this regard, ifsuch entity is for example in an aqueous environment, it is understoodthat the compound R—COOH is in such same medium, and therefore theentity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, and any othergroup that interacts or transforms according to known manners in themedium that contains the compound. Such interactions and transformationsinclude, but are not limited to, dissociation, association, tautomerism,solvolysis, including hydrolysis, solvation, including hydration,protonation and deprotonation. No further examples in this regard areprovided herein because these interactions and transformations in agiven medium are known by any one of ordinary skill in the art.

In another example, a “zwitterionic” compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI: 27369 by the Chemical Entitiesof Biological Interest (ChEBI) dictionary of molecular entities. As isgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion +H₃NCH₂COO—. Zwitterions, zwitterionic compounds,inner salts, and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of said element. Any formulagiven herein is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine, sulfur, fluorine, chlorine andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶C, ¹²⁵I, respectively.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of species for the same variable elsewherein the formula, unless otherwise stated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S4; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂ and “S² _(example) is one of S₃ and S₄ isaccordingly used herein for the sake of brevity but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴ R^(a), R^(b), R^(c), R^(d), R^(d1), R^(e), R^(e1), R^(f),R^(g), R^(h), R^(i), R^(j), R^(k), R^(m), R^(n) and U, Y, Z, HAL, HETand any other generic substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂ and S₃, the listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂ and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴, R^(a), R^(b), R^(c), R^(d), R^(d1), R^(e), R^(e1), R^(f),R^(g), R^(h), R^(j), R^(k), R^(m), R^(n) and U, Y, Z, HAL, HET and anyother generic substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with the total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the second memberand B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)).

A “pharmaceutically acceptable prodrug” is a prodrug that is preferablynon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “metabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or salt thereof. Preferably, themetabolite is in an isolated form outside the body.

Compostions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula (I) and a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn etal., Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672;Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19; Stahland Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use:2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011). Examples ofpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. A compound of Formula(I) may possess a sufficiently acidic group, a sufficiently basic group,or both types of functional groups, and accordingly react with a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt bases, and inorganic and organicacids, to form a pharmaceutically acceptable salt.

The term “carrier” refers to an adjuvant, vehicle, or excipients, withwhich the compound is administered. In preferred embodiments of thisinvention, the carrier is a solid carrier. Suitable pharmaceuticalcarriers include those described in Remington: The Science and Practiceof Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include, for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition”. For example, a CNS disorder also means a CNSdisease or a CNS condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The terms “treating,” “treatment,” and “treat” cover therapeutic methodsdirected to a disease-state in a subject and include: (i) preventing thedisease-state from occurring, in particular, when the subject ispredisposed to the disease-state but has not yet been diagnosed ashaving it; (ii) inhibiting the disease-state, e.g., arresting itsdevelopment (progression) or delaying its onset; and (iii) relieving thedisease-state, e.g., causing regression of the disease state until adesired endpoint is reached. Treating also includes ameliorating asymptom of a disease (e.g., reducing the pain, discomfort, or deficit),wherein such amelioration may be directly affecting the disease (e.g.,affecting the disease's cause, transmission, or expression) or notdirectly affecting the disease.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect.

In methods of treatment according to the invention, “an effectiveamount” of at least one compound according to the invention isadministered to a subject (e.g., a mammal). An “effective amount” alsomeans an amount or dose of a compound or composition effective tomodulate activity of PDE4 or an associated signaling pathway, such asthe CREB pathway and thus produce the desired modulatory effect. The“effective amount” will vary, depending on the compound, the disease,the type of treatment desired, and its severity, and age, weight, etc.

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

By “enhance,” “enhancing,” or “enhancement” is meant the ability topotentiate, increase, improve or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to thenormal long term memory formation of the animal or controls. As aresult, long term memory acquisition is faster or better retained.Enhancing performance of a cognitive task refers to the ability topotentiate or improve performance of a specified cognitive task by ananimal relative to the normal performance of the cognitive task by theanimal or controls.

As used herein, the term “training protocol,” or “training,” refers toeither “cognitive training” or “motor training.” The phrase “inconjunction” means that a compound or composition of the presentinvention enhances CREB pathway function during cognitive or motortraining.

Reference will now be made to the embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying drawings and examples. While certain embodiments aredescribed herein, it is understood that the described embodiments arenot intended to limit the scope of the invention. On the contrary, thepresent disclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

Compounds

The present invention provides certain substituted pyridine andpyriazine derivatives, which are useful, for example, as inhibitors ofPDE4 enzymatic activity. They are distinct from tri-substitutedpyridines are disclosed in the following publications: U.S. Pat. No.7,399,761 (Novartis AG, Nov. 14, 2002, CAS No. 1106203-18-2,1106203-.16-0); Intl. Pat. Appl. Publ. WO 2003050098, (MaxiaPharmaceuticals, Jun. 19, 2003, CAS No. 544475-13-0, 544475-12-9) and JPPat. 4,321,737 (Intl. Pat. Appl. Publ. WO 9931062, Shionogi & Co., Jun.24, 1999, CAS No. 228096-03-5, 228096-04-6).

In its many embodiments, the invention is directed to a chemical entityof Formula (I):

wherein:

-   Z is CH or N;    -   i) wherein when Z is CH, then;-   R¹ is a member selected from the group consisting of: —H, —C₁₋₃alkyl    and —C₁₋₃haloalkyl;-   Y is —C(R^(a))₂—, where each R^(a) is independently selected from    the group consisting of: —H, —F, —CH₃, —OH and —N(R^(b))₂;-   R² is a member selected from the group consisting of:    -   A) phenyl unsubstituted or substituted with one or two R^(c)        members, where each R^(c) is independently selected from the        group consisting of: halo, —CN, —CO₂R^(b), —CONH₂, —SO₂CH₃.        —C(R^(b))₂OH, —CH₂NH₂, —CH₂CONH₂, —CH₂CO₂C₁₋₃alkyl, —NHCONH₂,        —NHCONH-oxetane, —CONH-oxetane,

-   -   B) six-membered monocyclic heteroaromatic ring containing one or        two nitrogen members unsubstituted or substituted with one or        two members each independently selected from the group        consisting of: halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl, —CN, —OH,        —C(R^(b))₂OH, —CH₂NH₂, —C(R^(b))₂CN, —C(R^(b))₂CONH₂,        —OCH₂CONH₂, —OC₁₋₃alkyl, —OCH₂C(R^(b))₂OH, —OCH₂cyclopropyl,        —OC₁₋₃haloalkyl, —CO₂H, —CON(R^(b))₂, —N(R^(b))₂, —NHCH₂CF₃,        —NHCH(CH₃)₂, —NHCH₂CH₂N(CH₃)₂, —NHCH₂CH₂OH, —NHcyclopropyl,        —NHCOCH₃, morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;    -   C) five-membered monocyclic heteroaromatic ring containing two,        three, or four nitrogen members unsubstituted or substituted        with one or two members each independently selected from the        group consisting of halo, —C₁₋₃alkyl, —C₁₋₃haloalkyl,        —C(R^(b))₂OH, —N(R^(b))₂, —NO₂, —CN, —CH₂CN, —OC₁₋₃alkyl,        —CH₂OCH₃. —CH₂CH₂OH, —CH₂NH₂, —CH₂CONH₂, —CO₂C₁₋₃alkyl, —CO₂H,        —CONH₂, —NHCOCH₃, and cyclopropyl; and    -   D) five or six-membered ring selected from:        1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted        or substituted with one or two members each independently        selected from the group consisting of —CH₃, and —NH₂;

-   R³ is phenyl or pyridine, substituted with one or two members each    independently selected from the group consisting of: -halo,    —C₁₋₃alkyl, —OC₁₋₃alkyl, -Ocyclopropyl, —O-oxetane, —C₁₋₃haloalkyl,    —OC₁₋₃haloalkyl, —CN, —CH₂OH, —SO₂CH₃, or —N(CH₃)₂;

-   R⁴ is a member selected from the group consisting of —C₁₋₃alkyl and    —C₁₋₃haloalkyl; and

-   each R^(b) is independently selected from —H or —CH₃;

-   ii) wherein when Z is N, then;

-   R¹ is —H;

-   Y is —CH₂—;

-   R² is a member selected from the group consisting of:    -   A) phenyl substituted with one or two R^(d) members, where each        R^(d) is independently selected from the group consisting of:        —CN, —CONH₂, and —CO₂C₁₋₃alkyl;    -   B) six-membered monocyclic heteroaromatic ring containing one or        two nitrogen members unsubstituted or substituted with a member        selected from the group consisting of: —CN, —OC₁₋₃alkyl, —CONH₂,        —NHCH₂CH₂OH, —N(R^(b))₂, and —NH-cyclopropyl;    -   C) five-membered monocyclic heteroaromatic ring containing two        or three nitrogen members unsubstituted or substituted with one        or two members each independently selected from the group        consisting of —C₁₋₃alkyl, —C₁₋₃haloalkyl, —CH₂OR^(b),        —N(R^(b))₂, —NO₂, —CO₂CH₃, —CO₂N(R^(b))₂, or cyclopropyl; and    -   D) 1,2-oxazole optionally substituted with one or two R^(b)        members;    -   R³ phenyl substituted with one or two members each independently        selected from the group consisting of: —Cl, —OC₁₋₃alkyl, or        —OC₁₋₃haloalkyl;

-   R⁴ is —C₁₋₃alkyl; and

-   each R^(b) is independently selected from —H or —CH₃.

In certain embodiments of compounds of Formula (I), Z is CH.

In certain embodiments of compounds of Formula (I), Z is N.

Some embodiments are given by compounds of Formula (I) where Z is CH,and R¹ is —H, —CH₃, or —CF₃.

In some of these embodiments, R¹ is —H.

In certain embodiments of compounds of Formula (I), Y is —CH₂—, —CH(F)—,—CH(OH)—, —C(OH)(CH₃)—, or —CH(CH₃)—, and Z is CH.

In some of these embodiments, Y is —CH₂— and Z is N.

In certain embodiments of compounds of Formula (I), R² is

and R^(c) is halo, —CN, —CO₂H, —(CH₂)₀₋₁CONH₂, —SO₂CH₃, —C(R^(b))₂OH,—CH₂NH₂, —CH₂CO₂C₁₋₄alkyl, —NHCONH₂, —NHCONH-oxetane, —CONH-oxetane,

In some of these embodiments, R² is

and R^(c) is —F, —(CH₂)₀₋₁CONH₂, —CH₂NH₂, —C(CH₃)₂OH, —SO₂CH₃, or—NHCONH₂.

In certain embodiments of compounds of Formula (I), Z is N and R² is4-cyanophenyl, 4-phenylamide or 4-phenylcarboxylic acid methyl ester.

Some embodiments are given by compounds of Formula (I) where R² ispyridine, unsubstituted or substituted with one or two members eachindependently selected from: —F, —C₁₋₆alkyl, —C₁₋₃haloalkyl,—OC₁₋₆alkyl, —OCH₂cyclopropyl, —CN, —N(R^(b))₂, —CH₂NH₂, —CO₂H,—CON(R^(b))₂, or —C(R^(b))₂OH.

In some of these embodiments, R² is

and R^(d) is —C₁₋₆alkyl, —CF₃, —CN, —N(R^(b))₂, —CO₂H, —CON(R^(b))₂,—OC₁₋₃alkyl, —CH₂NH₂, —C(R^(b))₂OH, —OCH₂cyclopropyl, or —OCH(CH₃)₂.

In some of these embodiments, R² is

and R^(d) is —CH₃, —CF₃, —NH₂, —NHCH₃, —N(CH₃)₂, —CONH₂, —CONHCH₃,—CON(CH₃)₂, —OC₁₋₃alkyl, —CH₂OH, —C(CH₃)₂OH, or —OCH₂cyclopropyl.

In some of these embodiments, Z is N, and R² is

R^(d1) is —CN or —CONH₂.

Some embodiments are given by compounds of Formula (I), where R² isselected from the group consisting of pyrazine, pyridazine andpyrimidine; where pyrazine is optionally unsubstituted or substitutedwith —C₁₋₃alkyl, —OC₁₋₃alkyl, —N(R^(b))₂, or —NHCH₂CH₂OH; pyridazine isoptionally unsubstituted or substituted with —C₁₋₃alkyl; and pyrimidineis optionally substituted with a group consisting of: —H, halo,—C₁₋₃alkyl, —CN, —OH, —OC₁₋₃alkyl, —OC₁₋₃haloalkyl, —CO₂H, —CON(R^(b))₂,—C(R^(b))₂CONH₂, —C(R^(b))₂OH, —C(R^(b))₂CN, —CH₂CH₂N(CH₃)₂,—OCH₂C(R^(b))₂OH, —OCH₂CONH₂, —N(R^(b))₂, —NHCH₂CF₃, —NHCH(CH₃)₂,—NHCH₂CH₂OH, —NHcyclopropyl, —NHCOCH₃, morpholinyl, pyrrolidin-3-ol, andazetidin-3-ol.

In some of these embodiments, R² is

unsubstituted or substituted with one or two R^(e) members, where eachR^(e) is independently —H, —Cl, —C₁₋₃alkyl, —CN, —OCH₃, —OC₁₋₃haloalkyl,—CO₂H, —CONH₂, —C(R^(b))₂CONH₂, —C(R^(b))₂OH, —C(R^(b))₂CN,—CH₂CH₂N(CH₃)₂, —OCH₂C(R^(b))₂OH, —OCH₂CONH₂, —N(R^(b))₂, —NHCH₂CF₃,—NHCH(CH₃)₂, —NHCH₂CH₂OH, —NHcyclopropyl, —NHCOCH₃, morpholinyl,pyrrolidin-3-ol, and azetidin-3-ol.

In some of these embodiments, Z is N, and R² is

unsubstituted or substituted with R^(e1), where R^(e1) is —CN, —OCH₃,—CONH₂, —NH₂, —NHCH₃, —NHCH₂CH₂OH, or —NHcyclopropyl.

In some of these embodiments, R² is

and R^(e) is —H, halo, —CH₃, —CN, —OH, —OCH₃, —OCHF₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHCH₂CF₃, —NHcyclopropyl, —C(CH₃)₂OH, —CONH₂, —CONHCH₃, or—CON(CH₃)₂.

Some embodiments are given by compounds of Formula (I) where R² isimidazole, pyrazole, triazole, and tetrazole, unsubstituted orsubstituted with one or two members each independently selected from thegroup consisting of: —Cl, —CH₃, —CHF₂, —CF₃, —CH₂OH, —CH₂CN, —CH₂CONH₂,—CH₂CH₂OH, —NH₂, —NO₂, —CN, —CO₂C₁₋₃alkyl, —CO₂H, —CONH₂, or —NHCOCH₃.

In some of these embodiments, R² is

and R^(f) is —H, —Cl, —CH₃, —NO₂, —NH₂, —NHCOCH₃, —CH₂OH, —CN, —CONH₂,—CO₂H, or —CO₂CH₂CH₃.

In some of these embodiments, R² is

and R^(f) is —H, —NH₂, or —CH₂OH.

In some of these embodiments, R² is

where R^(g) is —H, —CH₃, —CH₂OH, —CONH₂, or —NH₂.

Some embodiments are given by compounds of Formula (I) where R² is1H-tetrazole, 2H-tetrazole, 1,2-oxazole, 1,3-thiazole, eachindependently unsubstituted or substituted with —CH₃, —CH₂OH, —CH₂CH₂OHor —NH₂.

Some embodiments are given by compounds of Formula (I) where R² is1,2,3-triazole and 1,2,4-triazole, each independently unsubstituted orsubstituted with —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, —OCH₂CH₃, —CN, —CH₂CN,—CH₂CONH₂, —C(R^(b))OH, —CH₂OCH₃, N(R^(b))₂, —NO₂, —CO₂CH₃, —CONH₂,cyclopropyl or —CH₂NH₂.

In some of these embodiments, R² is

and R^(h) is —H, —CH₃, —CF₃, —CH₂F, —CHF₂, —OCH₃, —OCH₂CH₃, —CH₂OH,—C(CH₃)₂OH, —CH₂OCH₃, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —CN, —CH₂CN,—CH₂CONH₂, —CONH₂, —CO₂CH₃, or -cyclopropyl.

In some of these embodiments, R² is

and R^(j) is —H, —CH₃, —CF₃, —OCH₃, —CH₂(OH), —C(CH₃)₂OH, —CH₂OCH₃,—CO₂CH₃, or —NO₂.

In some of these embodiments, R² is

and R^(k) is —H, —CH₃, —CF₃, —CH₂F, —CHF₂, —OCH₃, —OCH₂CH₃, —CH₂OH,—C(CH₃)₂OH, —CH₂OCH₃, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —CN, —CONH₂,—CO₂CH₃, or -cyclopropyl.

Some embodiments are given by compounds of Formula (I) where R³ is

and R^(m) is —Cl, —F, —CH₃, —CHF₂, —CN, —OCH₃, —CH₂OH, —OCH₂CH₃, —OCF₃,—OCHF₂, —N(CH₃)₂, —SO₂CH₃, —OCH(CH₃)₂,

In some of these embodiments, R³ is a member selected from the groupconsisting of: 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl,3-methylphenyl, 3-(trifluoromethyl)phenyl, 3-methoxyphenyl,3-ethoxyphenyl, 3-(trifluoromethoxy)phenyl, 3-(difluoromethoxy)phenyl,3-(difluoromethyl)phenyl, 3-(dimethylamino)phenyl, 4-fluorophenyl,4-chlorophenyl, 5-chloropyridin-3-yl, 3,4-difluorophenyl,3,5-difluorophenyl, (3-fluoro-5-methoxyphenyl, 3-chloro-4-fluorophenyl,4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 4-fluoro-3-methylphenyl,4-fluoro-3-methoxyphenyl or 3-ethoxy-4-fluorophenyl.

Some embodiments are given by compounds of Formula (I) where R³ is

and R^(n) is H, —Cl, —CH₃, —CF₃, —OCH₃, —OCH₂CH₃, —OCHF₂, —OCF₃, or —CN.

Some embodiments are given by compounds of Formula (I) where R⁴ is —CH₃,—CH₂CH₃, —CH(CH₃)₂, or —CHF₂.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, a compound, or a pharmaceutically acceptablesalt thereof, of Formula (I), is selected from the group consisting of:

Ex # Compound Name 15-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile; 22-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine; 3{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine; 42-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 5 2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 62-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 72-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 8{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol; 93-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 102-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 112-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 122-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 135-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide; 14[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol; 151-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol; 16[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol; 17 {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine; 18[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4- fluorophenyl)methanamine;19 {[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine; 203-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2- methoxypyridine;21 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid; 225-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile; 235-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylic acid; 245-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 255-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2- amine;26 (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea; 274-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide; 283-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine; 295-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine; 305-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2- amine; 311-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea; 323-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3- yl)methyl]pyridine;33 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine; 345-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine; 355-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile; 365-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine; 37 (2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol; 385-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2- amine;39 5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile; 405-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2- amine;41 5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine; 425-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine; 435-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine; 44N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 45 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine; 465-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine; 475-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine; 482-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol; 493-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine; 503-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine; 513-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine; 525-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one; 533-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine; 545-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylic acid; 553-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine; 565-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine; 575-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine; 583-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine; 59 (4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine; 604-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2- amine; 613-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine; 624-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile; 634-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide; 643-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine; 653-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine; 663-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine; 673-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine; 683-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine; 693-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine; 705-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide; 71(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine; 723-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine; 733-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine; 743-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine; 755-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine; 765-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine; 775-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine; 785-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine; 793-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine; 803-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine; 815-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine; 825-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine; 835-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine; 845-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine; 85 Methyl4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2- yl]methyl}benzoate; 864-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile; 875-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2- amine;88 3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine; 895-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine; 905-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide; 915-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine; 925-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine; 935-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine; 945-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine; 953-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine; 963-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine; 973-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine; 983-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine; 993-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine; 100 Methyl2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate; 101 Ethyl1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate; 1023-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine; 1035-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile; 1045-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine; 1055-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2- amine;106 5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine; 1075-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile; 1085-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile; 109 3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine; 1102-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3- yl]methyl}pyrazine;111 6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine; 1123-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 1134-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide; 1145-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide; 1155-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide; 1165-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide; 117 5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide; 1185-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 119 5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide; 1205-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide; 1215-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide; 1225-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide; 1235-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide; 124 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide; 1255-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide; 1265-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide; 127 Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate; 1283-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine; 1293-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;130 3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine; 1313-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 1323-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine; 1333-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine; 1343-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine;135 3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 1363-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile;137 2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine; 1383-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine; 1393-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 140 Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate; 141 Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate; 1423-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine; 1433-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 1443-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine; 1453-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1463-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine; 1473-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine; 1483-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine; 1493-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine; 1503-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine; 1513-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1523-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1533-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine; 1543-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine; 1551-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile; 1563-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1573-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1583-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1593-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1603-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine; 1613-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine; 1623-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1633-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1643-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1653-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 1665-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine; 1671-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide; 168 Ethyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate; 1691-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile; 1702-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 171N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide; 1723-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine; 1732-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 1742-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine; 1752-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine; 1761-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one; 1775-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine; 1783-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine; 1793-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine; 1803-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine; 1813-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine; 1823-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine; 1833-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine; 1843-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine; 1855-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine; 1863-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 1873-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 1883-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 1893-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 190 Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate; 191 Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate; 1923-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine; 1933-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine; 194 Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate; 195 Methyl1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate; 196 Methyl1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate; 1971-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide; 198(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 199(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 200[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 201[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 202(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol; 203(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 204[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 205[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 206(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 207[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 208[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol; 209(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol; 210[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 211(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 2123-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine; 2133-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine; 2143-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine; 2153-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine; 2161-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine; 2171-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2181-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2191-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2201-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2211-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2223-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile; 2231-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2241-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2251-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine; 2261-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2271-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2281-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine; 2291-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine; 2301-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; 2311-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine; 2321-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine; 2334-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine; 2344-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine; 2351-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine; 2361-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine; 2371-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl-1H-1,2,4-triazol-3-amine; 2381-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine; 239(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine; 2401-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide; 2414-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide; 2425-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide; 2431-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide; 2442-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide; 2452-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol; 2462-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol; 2472-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol; 2482-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol; 2492-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol; 2503-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine; 2513-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine; 2522-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 2533-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine; 2543-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine; 2553-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine; 2563-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine; 2573-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine; 2583-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine; 2593-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine;260 [1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol; 261(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol; 262[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol; 263(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol; 264[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol; 265(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol; 2663-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine; 2671-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylic acid; 2681-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide; 269[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol; 270(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol; 271(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol; 272[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol; 273(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol; 274(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol; 275(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol; 2764-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3- yl]methyl}benzoicacid; 277(1-((6-Ethoxy-5-(2-fluorophenyl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol; 2785-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine; 279 5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine; 2802-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide; 2812-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 282 5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 2832-[(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol; 2842-(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)-2-methylpropanenitrile; 2852-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetonitrile; 2863-(3-Chlorophenyl)-5-[(5-ethoxypyridin-2-yl)methyl]-2- methoxypyridine;287 5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine; 288 5-((5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine; 2892-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-5- ethoxypyrazine;290 2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)amino)ethanol; 2913-(3-Chlorophenyl)-2-methoxy-5-((5-methyl-1H-tetrazol-1-yl)methylpyridine; 2924-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)pyrimidin-2-yl)morpholine; 2935-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-amine; 2942-((5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-yl)amino)ethanol; 2952-(1-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)ethanol; 2962-Ethoxy-3-(4-fluorophenyl)-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine; 2972′-(Difluoromethoxy)-5-((4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl)methyl)-2-methoxy-3,4′-bipyridine; 2982-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide; 299(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol; 300(1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol; 3015-((2′-(Difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine; 3025-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol; 3032-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)ethanol; 3045-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-2-(difluoromethoxy)pyrimidine; 3055-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine; 3063-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-fluoropyridin-3-yl)methyl]pyridine; 3071-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide; 3081-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide; 3091-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazole-3-carboxamide; 3101-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-imidazole-4-carboxamide; 3111-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-imidazole-4-carboxamide; 3121-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide; 3131-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-pyrazole-3-carboxamide; 3141-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide; 315[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazol-4-yl]methanol; 316[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-5-methyl-1H-pyrazol-3-yl]methanol; 3171-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine; 3181-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)oxy]-2-methylpropan-2-ol; 319(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-5-yl)methanol; 320(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-3-methyl-1H-pyrazol-5-yl)methanol; 321(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 322(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 323(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol; 324(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 325(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol; 326(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 327(1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 328(1-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 329(1-{[5-(5-Chloropyridin-3-yl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 330(1-{[5-(3,4-Dichlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 331(1-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 332[1-({6-Ethoxy-5-[3-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 333[1-({6-Ethoxy-5-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 334(1-{[6-Ethoxy-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 335[1-({5-[3-(Dimethylamino)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 336(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 337(1-{[5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 338(1-{[5-(3,5-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 339[1-({6-Ethoxy-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol; 340(1-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 341(1-{[6-Ethoxy-5-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 342(1-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol; 343(1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 344(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 345(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 346(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 3474-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile; 3482-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile; 3495-{[5-(2-Ethoxypyridin-4-yl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3505-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2- amine;351 5-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine; 352 5-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine; 3535-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine; 354 5-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3555-{[5-(3-Ethoxy-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3563-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile; 357 5-{[5-(4-Fluoro-3-methylphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3582-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile; 3595-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3605-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2- amine;361 5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 3625-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine; 363 2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide; 3642-(4-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide; 3652-(4-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide; 3662-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 3672-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)-2-methylpropanamide; 3682-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 3692-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 3702-(5-{[5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 3712-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide; 3722-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetamide; 3735-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 3745-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide; 375 2-[(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol; 376(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol; 377 2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-5-methylpyrazine; 3786-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-3-carbonitrile; 379 5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-amine; 3803-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 381(2-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; 382(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; 383(2-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; 384(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; 385(2-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; 386(1-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; 387(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol; 388(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol; 3891-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol; 3901-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)azetidin-3-ol; 3912-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol; 3922-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine; 3933-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine; 3943-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine; 3953-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3963-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3973-(4-Chloro-3-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3983-(3-Chloro-4-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 3993-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 4002-Ethoxy-3-(2-ethoxypyridin-4-yl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 4012-Ethoxy-3-(3-ethoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 4022-Ethoxy-3-(3-fluoro-5-methoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine; 4033-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine; 404(5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol; 405[5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanol; 406(1-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol; 4071-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine; Intermediate 49 Ethyl2-(4-{[5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate; Intermediate 50 Ethyl2-(4-{[5-(3-chlorophenyl)-6-methoxypyridin-3- yl]methyl}phenyl)acetate;and

Isotopically-Labeled Compounds

The invention also includes isotopically-labeled compounds, which areidentical to those recited in Formula I, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of carbon, chlorine, fluorine, hydrogen,iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium, including¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,³¹P, ³²P, ³⁵S, and ^(99m)Tc.

Compounds of the present invention (and derivatives of such compounds,such as pharmaceutically acceptable salts and prodrugs) that contain theaforementioned isotopes or other isotopes of other atoms are within thescope of the invention. Isotopically-labeled compounds of the presentinvention are useful in drug and substrate tissue distribution andtarget occupancy assays. For example, isotopically labeled compounds areparticularly useful in SPECT (single photon emission computedtomography) and in PET (positron emission tomography), as discussedfurther herein.

Derivatives

The present invention also provides derivatives of a chemical entity ofFormula (I), which include, but are not limited to, any salt, solvate,conformer, or crystalline form/polymorph.

Salts

Accordingly, in one embodiment the invention includes pharmaceuticallyacceptable salts of the compounds represented by Formula (I), andmethods using such salts.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-O-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Solvates

In other embodiments, the invention provides a solvate of a compound ofFormula (I), and the use of such solvates in methods of presentinvention. Certain compounds of Formula (I) or pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained assolvates. In some embodiments, the solvent is water and the solvates arehydrates.

More particularly, solvates include those formed from the interaction orcomplexes of compounds of the invention with one or more solvents,either in solution or as a solid or crystalline form. Such solventmolecules are those commonly used in the pharmaceutical art, which areknown to be innocuous to the recipient, e.g., water, ethanol, ethyleneglycol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such as MeOH,methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propyleneglycol, (R)-propylene glycol, 1,4-butyne-diol, and the like. Hydratesinclude compounds formed by an incorporation of one or more watermolecules.

Conformers and Crystalline Forms/Polymorphs

In other embodiments, the invention provides conformer and crystallineform of a compound of Formula (I), and the use of these derivatives inmethods of present invention. A conformer is a structure that is aconformational isomer. Conformational isomerism is the phenomenon ofmolecules with the same structural formula but different conformations(conformers) of atoms about a rotating bond.

A polymorph is a composition having the same chemical formula, but adifferent solid state or crystal structure. In certain embodiments ofthe invention, compounds of Formula (I) were obtained in crystallineform. In addition, certain crystalline forms of compounds of Formula (I)or pharmaceutically acceptable salts of compounds of Formula (I) may beobtained as co-crystals. In still other embodiments, compounds ofFormula (I) may be obtained in one of several polymorphic forms, as amixture of crystalline forms, as a polymorphic form, or as an amorphousform.

Prodrugs

The invention also relates to prodrugs of the compounds of Formula (I),and the use of such pharmaceutically acceptable prodrugs in methods ofthe present invention, particularly therapeutic methods. Exemplaryprodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, desmosine, isodesmosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₆alkyl, C₁₋₆cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130.

Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J. Med. Chem. 1996, 39, 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

Prodrugs may be determined using routine techniques known or availablein the art (e.g., Bundgaard (ed.), 1985, Design of prodrugs, Elsevier;Krogsgaard-Larsen et al., (eds.), 1991, Design and Application ofProdrugs, Harwood Academic Publishers).

Metabolites

The present invention also relates to a metabolite of a compound ofFormula (I), as defined herein, and salts thereof. The present inventionfurther relates to the use of such metabolites, and salts thereof, inmethods of present invention, including therapeutic methods.

Metabolites of a compound may be determined using routine techniquesknown or available in the art. For example, isolated metabolites can beenzymatically and synthetically produced (e.g., Bertolini et al., J.Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86,765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; and Bodor, Adv DrugRes. 1984, 13, 224-231).

Compositions

In some embodiments Compounds of Formula (I) and pharmaceuticallyacceptable salts thereof are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions. A pharmaceutical composition of the invention comprises:(a) an effective amount of at least one active agent in accordance withthe invention; and (b) a pharmaceutically acceptable excipient.

Formulations and Administration

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe (GRAS) to be administered to ananimal. In general, safe solvents are non-toxic aqueous solvents such aswater and other non-toxic solvents that are soluble or miscible inwater. Suitable aqueous solvents include water, ethanol, propyleneglycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixturesthereof. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid, and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent with avariety of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, common methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the compounds of Formula (I) can be determined bycomparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art. Useful dosages of the compoundsof formula I can be determined by comparing their in vitro activity, andin vivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart (e.g., U.S. Pat. No. 4,938,949). Useful dosages of PDE4 inhibitorsare known to the art (e.g., U.S. Pat. Nos. 7,829,713; 8,338,405).

Optimal dosages to be administered in the therapeutic methods of thepresent invention may be determined by those skilled in the art and willdepend on multiple factors, including the particular composition in use,the strength of the preparation, the mode and time of administration,and the advancement of the disease or condition. Additional factors mayinclude characteristics on the subject being treated, such as age,weight, gender, and diet.

In general, however, a suitable dose will be in the range from about0.01 to about 100 mg/kg, more specifically, from about 0.1 to about 100mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about50 mg per kilogram body weight of the recipient per day, 0.5 to 90mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of valuestherein). The compound is conveniently administered in a unit dosageform; for example, containing about 1 to 1000 mg, particularly about 10to 750 mg, and more particularly, about 50 to 500 mg of activeingredient per unit dosage form.

Preferably, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, and more preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 1 to 100mg of the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01 to 5.0 mg/kg/hr or byintermittent infusions containing about 0.4 to 15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. Such compositions and preparations should contain atleast 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful composition is such thatan effective dosage level will be obtained. An exemplary dose is in therange from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from 1 to 200 mg/day,or about 5 to 50 mg/day.

Methods and Uses Uses of Isotopically-Labeled Compounds

In one aspect, the present invention provides a method of usingisotopically labeled compounds and prodrugs of the present invention in:(i) metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H); (ii) detection or imaging techniques [suchas positron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays; or (iii) in radioactive treatment of patients.

Isotopically labeled compounds and prodrugs of the invention thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET, and an I¹²³ labeled compound may beparticularly preferred for SPECT studies. Further substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.

Therapeutic Methods Generally

In certain embodiments the present invention provides therapeuticmethods of using a compound of Formula (I) and its pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites, whether alone or in combination(collectively, “active agents”) of the present invention are useful asinhibiting PDE4 in the methods of the invention. Such methods forinhibiting PDE4 comprising administering to an animal an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).Embodiments of this invention inhibit PDE4. The invention furtherincludes the use of such compounds and compositions thereof in themethods described herein. In one aspect of such methods disclosedherein, the animal is healthy. In another aspect of such methods, theanimal has a disorder. In another aspect of all such methods the animalis an aged animal. In preferred embodiments the animal in such methodsis a human.

In one aspect, such chemical entities are useful as inhibitors of PDE4enzymes. Accordingly, the present invention provides a method forinhibiting PDE4, comprising administering to an animal an effectiveamount of a chemical entity of Formula (I) or composition thereof.

Chemical entities of the present invention may be administered as amono-therapy or as part of a combination therapy. In one aspect, one ormore of the compounds (or salts, prodrugs, or metabolites thereof) ofthe present invention may be co-administered or used in combination withone or more additional therapies known in the art.

Compounds of the present invention may also be used as adjunct therapy,for example, with other PDE inhibitors.

The present invention also includes methods of treating a disease,disorder, or condition mediated by PDE4. Accordingly, in one embodiment,the invention provides a method of treating a disorder mediated by PDE4in particular, comprising administering to an animal in need of suchtreatment an effective amount of a chemical entity of Formula (I) orcomposition of the present invention.

In certain embodiments, the present invention includes the use of achemical entity of Formula (I) in the manufacture of a medicament fortreating a disease, condition, or disorder by inhibiting PDE4 Thepresent invention further provides a method of administering atherapeutically effective amount of a medicament of the presentinvention to a patient in need of such treatment to treat the disorder.

In one aspect, the compounds of the present invention are useful inenhancing neuronal plasticity—an essential property of the brain thatcan be augmented in healthy animals and can be impaired in numerous CNSdisorders. For example, by inhibiting PDE4, a compound of the presentinvention can increase levels of cAMP, modulating cyclic nucleotidesignaling cascades.

More particularly, the ability of extracellular signals to modulate theintracellular concentration of cyclic nucleotides allows cells torespond to external stimuli across the boundary of the cell membrane.The cyclic nucleotide signaling cascades have been adapted to respond toa host of transduction systems including G-protein coupled receptors(GPCRs) and voltage and ligand gated ion channels. Cyclic nucleotidestransmit their signal in the cell through a variant of tertiaryelements. The best described of these are cAMP dependent protein kinase(PKA) and cGMP dependent protein kinase (PKG). The binding of the cyclicnucleotide to each enzyme enables the phosphorylation of downstreamenzymes and proteins functioning as effectors or additional elements inthe signaling cascade. Of particular importance to memory formation iscAMP-dependent activation of PKA, which phosphorylates CREB. pCREB is anactivated transcription factor, which binds to specific DNA loci andinitiates transcription of multiple genes involved in neuronalplasticity (e.g., Tully et al., Nat. Rev. Drug. Discov. 2003, 2,267-277; and Alberini, Physiol. Rev. 2009, 89, 121-145).

Consistent with these observations, both in vitro and in vivo studieshave associated alterations in cyclic nucleotide concentrations withbiochemical and physiological process linked to cognitive function(Kelly and Brandon, Progress in Brain Research, 2009, 179, 67-73;Schmidt, Current Topics in Medicinal Chemistry, 2010, 10, 222-230).Moreover, signal intensity and the levels of coincident activity at asynapse are established variables that can result in potentiation oftransmission at a particular synapse. Long term potentiation (LTP) isthe best described of these processes and is known to be modulated byboth the cAMP and cGMP signaling cascades.

Accordingly, the present invention provides a method of enhancingneuronal plasticity, comprising administering to an animal in needthereof an effective amount of a chemical entity or composition of thepresent invention.

In another embodiment, the present invention provides a method oftreating a disease mediated by PDE4, comprising administering to ananimal in need of such treatment an effective amount of a compound orcomposition of the present invention. PDE4-related indications that canbe treated by compounds and compositions of the present inventioninclude, but are not limited to neurological disorders, inflammatorydisorder, renal disorder, and other disorders involving PDE4.

Chemical entities and compositions of the present invention are alsouseful as neuroprotective agents, as described in greater detail herein.Accordingly, the present invention provides a method of neuroprotection,comprising administering to an animal in need thereof an effectiveamount of at least one chemical entity or composition of the presentinvention.

Chemical entities and compositions of the present invention are alsouseful as agents in neurorehabilitation and neurorecovery, as describedin greater detail herein. Accordingly, the present invention provides amethod of neurorehabilitation or neurorecovery, comprising administeringto an animal in need thereof an effective amount of at least onechemical entity or composition of the present invention.

In addition, such compounds can be administered in conjunction withtraining protocols to treat cognitive or motor deficits associated withCNS disorders, as described in more detail herein. In addition, suchcompounds can be used to enhance the efficiency of training protocols innon-human animals, in particular healthy non-human animals, as describedherein.

Neurological Disorders

In some embodiments, the present invention provides a method of treatinga neurological disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or compositiondescribed herein.

A neurological disorder (or condition or disease) is any disorder of thebody's nervous system. Neurological disorders can be categorizedaccording to the primary location affected, the primary type ofdysfunction involved, or the primary type of cause. The broadestdivision is between central nervous system (CNS) disorders andperipheral nervous system (PNS) disorders.

Neurological disorders include structural, biochemical, or electricalabnormalities in the brain, spinal cord or other nerves, abnormalitiesthat can result in a range of symptoms. Examples of such symptomsinclude paralysis, muscle weakness, poor coordination, loss ofsensation, seizures, confusion, pain, altered levels of consciousness,and cognitive deficits, including memory impairments. There are manyrecognized neurological disorders, some relatively common, but manyrare. They may be assessed by neurological examination, and studied andtreated within the specialties of neurology and clinicalneuropsychology.

Neurological disorders and their sequelae (direct consequences) affectas many as one billion people worldwide, as estimated by the WorldHealth Organization in 2006. Interventions for neurological disordersmay include, in addition to medications, preventative measures,lifestyle changes, physiotherapy or other therapies,neurorehabilitation, pain management, and surgery.

Neurological disorders include, but are not limited to the following(which are not necessarily mutually exclusive): psychiatric disorders,such as mood disorders, psychotic disorders, and anxiety disorders;personality disorders; substance-related disorders; dissociativedisorders; eating disorders; sleep disorders; developmental disorders;neurodegenerative disorders, including movement disorders;trauma-related disorders; pain disorders; and cognitive disorders, acategory that includes memory disorders such as AAMI and MCI, as well ascognitive deficits (particularly memory deficits) associated with CNSdisorders.

Psychiatric Disorders

In one embodiment, the invention provides a method of treating apsychiatric disorder, comprising administering to an animal in need ofsuch treatment an effective amount of a compound or pharmaceuticalcomposition described herein. Psychiatric disorders include mood (oraffective) disorders, psychotic disorders, and anxiety (or neurotic)disorders.

Mood Disorders

In some embodiments, the psychiatric disorder is a mood (or affective)disorder. Accordingly, the present invention provides a method oftreating a mood disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or pharmaceuticalcomposition described herein. In a specific aspect, the mood disorder isa depressive disorder, including a dysthymic disorder, major depressivedisorder (recurrent and single episode), mania, bipolar disorders (I andII), and cyclothymic disorder. Long-standing research underscores a rolefor PDE4 in mood disorders, including depressive disorders, bipolardisorders, and substance induced mood disorders is known in theliterature.

A specific embodiment of the invention is a method of treating asubstance induced mood disorder, comprising administering to an animalin need of such treatment a therapeutically effective amount of acompound or pharmaceutical composition described herein. The utility ofPDE4 inhibitors in the treatment of substance induced mood disorders isknown in the literature.

Psychotic Disorders

In some embodiments, the psychiatric disorder is a psychotic disorder.Accordingly, the present invention provides a method of treating apsychotic disorder, comprising an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. In a specific aspect, the psychotic disorder is one or more ofthe following: schizophrenia; schizophreniform disorder; schizoaffectivedisorder, delusional disorder; brief psychotic disorder, sharedpsychotic disorder; substance-induced psychotic disorders, such as apsychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, inhalants, opioids, or phencyclidine; and personalitydisorders at times of stress (including paranoid personality disorder,schizoid personality disorder, and borderline personality disorder).

A specific embodiment of the invention is a method of treating adelusional disorder, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of delusional disorders is known in theliterature.

A particular embodiment of the invention is a method of treatingschizophrenia, comprising administering to an animal in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of schizophrenia, including schizophreniformdisorder and schizoaffective disorder, is known in the literature.

Anxiety Disorders

In some embodiments, the psychiatric disorder is an anxiety (orneurotic) disorder. Accordingly, the present invention provides a methodof treating an anxiety disorder, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, theanxiety disorder is one or more of the following: panic disorder,specific phobia, social phobia, obsessive-compulsive disorder,generalized anxiety disorder, post-traumatic stress disorder, and acutestress disorder. The use of PDE4 inhibitors in the treatment of anxietyis known in the literature.

Personality Disorders

In some embodiments, the neurological disorder is a personalitydisorder. Accordingly, the present invention provides a method oftreating a personality disorder, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In particular embodiments,the personality disorder is one or more of the following: includes thoseof Cluster A (odd or eccentric), such as paranoid or schizoidpersonality disorder, those of Cluster B (dramatic, emotional, orerratic), such as antisocial, borderline, or narcissistic personalitydisorder, and those of Cluster C (anxious or fearful), such as avoidant,dependent, or obsessive-compulsive personality disorder.

Substance Related Disorders

In some embodiments, the neurological disorder is a substance-relateddisorder. Accordingly, a specific embodiment of the invention is amethod of treating a substance-related disorder, comprisingadministering to an animal in need of such treatment an effective amountof a compound or pharmaceutical composition described herein.

More particularly, the substance-related disorder includes one or moreof the following: an alcohol-related disorder, such as abuse,dependence, and withdrawal; an amphetamine (or amphetamine-related)disorder, such as abuse, dependence and withdrawal, a cocaine-relateddisorder, such as abuse, dependence and withdrawal; ahallucinogen-related disorder, such as abuse, dependence and withdrawal;an inhalant-related disorder, such as dependent and withdrawal; anicotine-related disorder, such as dependence and withdrawal; anopioid-related disorder, such as abuse, dependence and withdrawal; aphencyclidine (or phencyclidine-like) related disorder, such as abuseand dependence; and a sedative-, hypnotic-, or anxiolytic-relateddisorder, such as abuse, dependence, and withdrawal.

In a specific embodiment, the compounds and compositions of the presentinvention are useful as an aid to a treatment of smoking cessation.Accordingly, the present invention provides a method of treating smokingaddiction, comprising administering to an animal in need thereof aneffective amount of a compound or composition of the present invention.

Dissociative Disorders

In some embodiments, the neurological disorder is a dissociativedisorder. Accordingly, a specific embodiment of the invention is amethod of treating a dissociative disorder, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, thedissociative disorder includes one or more of the following:depersonalization disorder, dissociative amnesia, and dissociativeidentity disorder.

Eating Disorders

In some embodiments, the neurological disorder is an eating disorder.Accordingly, a specific embodiment of the invention is a method oftreating an eating disorder, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, theeating disorder is anorexia nervosa or bulimia nervosa. The utility ofPDE4 inhibitors in the treatment of eating disorders is known in theliterature.

Sleep Disorders

In some embodiments, the neurological disorder is a sleep disorder.Accordingly, a specific embodiment of the invention is a method oftreating a sleep disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or pharmaceuticalcomposition described herein. More particularly, the sleep disorderincludes a primary sleep disorder, such as primary hypersomnia, primaryinsomnia, and narcolepsy; a parasomnia, such as a nightmare or sleepterror disorder; and other sleep disorders. The utility of PDE4inhibitors in the treatment of sleep disorders is known in theliterature.

In other embodiments, the sleep disorder is restless leg syndrome.Restless legs syndrome (RLS) is a disorder of the part of the nervoussystem that affects the legs and causes an urge to move them. Peoplewith restless legs syndrome have uncomfortable sensations in their legs(and sometimes arms or other parts of the body) and an irresistible urgeto move their legs to relieve the sensations. The sensations are usuallyworse at rest, especially when lying or sitting. The sensations can leadto sleep deprivation and stress. Because it usually interferes withsleep, it also is considered a sleep disorder. Accordingly, the presentinvention provides a method of treating restless leg syndrome,comprising administering to an animal in need thereof an effectiveamount of a compound or composition of the present invention.

Developmental Disorders

In some embodiments, the neurological disorder is a developmentaldisorder. Accordingly, a specific embodiment of the invention is amethod of treating a developmental disorder, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

More particularly, the developmental disorder is one or more of thefollowing: mental retardation, including mild, moderate, and severeforms; a learning disorder, such as that affecting reading, mathematics,or written expression; a motor skill disorder, such as developmentalcoordination disorder; a communication disorder; a pervasivedevelopmental disorder, such as an autistic disorder, Rhett's disorder,childhood disintegrative disorder, and Asperger's disorder, anattention-deficit or disruptive disorder, such as attention-deficithyperactivity disorder; and a tic disorder, such as Tourette's disorder,chronic motor disorder, or vocal tic disorder.

A specific embodiment of the invention is a method of treating anautistic disorder, comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein. In another embodiment, the inventionprovides a method of treating an attention-deficit hyperactivitydisorder, comprising administering to an animal in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of attention-deficit hyperactivity disorderis known in the literature.

Neurodegenerative Disorders

In particular embodiments, the invention provides a method of treating aneurodegenerative disorder, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

In one aspect, neurodegenerative disorders include Alzheimer's disease,Amyotrophic lateral sclerosis, corticobasal degeneration, chronictraumatic encephalopathy, and a disorder associated with repetitive headinjury.

Alzheimer's Disease

In a specific embodiment, the invention provides a method of treatingAlzheimer's disease, comprising administering to an animal in need ofsuch treatment an effective amount of a compound or pharmaceuticalcomposition described herein. A detailed set of criteria for thediagnosis of Alzheimer's is set forth in the Diagnostic and StatisticalManual of Mental Disorders (Fourth Edition, text revision (2000), alsoknown as the DSM-IV-TR). First, multiple cognitive deficits must bepresent, one of which must be memory impairment. Second, one or more ofthe following must be present: aphasia (deterioration of languageabilities); apraxia (difficulty executing motor activities—even thoughmovement, senses, and the ability to understand what is being asked arestill intact); or agnosia (impaired ability to recognize or identifyobjects—even though sensory abilities are intact).

Amyotrophic Lateral Sclerosis

In another specific embodiment, the invention provides a method oftreating amyotrophic lateral sclerosis, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig'sDisease,” is a progressive neurodegenerative disease that affects nervecells. Motor neurons reach from the brain to the spinal cord and fromthe spinal cord to the muscles throughout the body. As motor neuronsdegenerate, they can no longer send impulses to the muscle fibers thatnormally result in muscle movement.

Early symptoms of ALS often include increasing muscle weakness,especially involving the arms and legs, speech, swallowing or breathing.The progressive degeneration of the motor neurons in ALS eventuallyleads to their death. When the motor neurons die, the ability of thebrain to initiate and control muscle movement is lost. With voluntarymuscle action progressively affected, patients in the later stages ofthe disease may become totally paralyzed.

Movement Disorders

In other embodiments, the invention provides a method of treating amovement disorder, comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein. In one aspect, the movement disorderincludes one or more of the following: Huntington's disease, Parkinson'sdisease, an essential tremor, a Lewy body disease, hypokinetic disease,Multiple Sclerosis, various types of Peripheral Neuropathy, dystonia, abasal ganglia disorder, hypokinesia (including akinesia), anddyskinesia. In addition, Tourette's syndrome and other tic disorders canbe included as categories of movement disorders. The utility of PDE4inhibitors in the treatment of movement disorders is known in theliterature.

In related embodiment, the invention provides a method of treatingchorea, comprising administering to an animal in need of such treatmentan effective amount of a compound or pharmaceutical compositiondescribed herein. Chorea can occur in a variety of conditions anddisorders, and is a primary feature of Huntington's disease, aprogressive neurological disorder.

Huntington's Disease

In a specific embodiment, the present invention provides a method oftreating Huntington's disease, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Huntington's Disease (HD, or Huntington chorea) is a disorder passeddown through families in which nerve cells in certain parts of the brainwaste away, or degenerate. It is caused by a genetic defect onchromosome 4, causing a CAG repeat, to occur many more times thannormal. The CAG element is normally repeated 10 to 28 times, but inpersons with Huntington's disease, is repeated 36 to 120 times.

There are two forms of Huntington's disease: adult-onset Huntington'sdisease—which is the most common form and usually begins in the mid 30sand 40s; and early-onset Huntington's disease, which accounts for asmall number of cases and begins in childhood or adolescence.

Symptoms of Huntington's disease include behavioral changes, abnormaland unusual movements, and worsening dementia. Behavioral changes mayinclude behavioral disturbances, hallucinations, irritability,moodiness, restlessness or fidgeting, paranoia, and psychosis. Abnormaland unusual movements include facial movements, such as grimaces; headturning to shift eye position; quick, sudden, sometimes wild jerkingmovements of the arms, legs, face, and other body parts; slow,uncontrolled movements; and unsteady gait. Worsening dementia includes;disorientation or confusion; loss of judgment; loss of memory;personality changes; and speech changes (e.g., Dumas et al., FrontBiosci (Schol Ed) 2013, S, 1-18). The utility of PDE4 inhibitors intreating Huntington's disease is known in the art.

Parkinson's Disease

In a specific embodiment, the present invention provides a method oftreating Parkinson's disease, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

In another embodiment, the invention provides a method of treatingmyoclonus, Gilles de la Tourette's syndrome, dystonia, or tics,comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of PDE4 inhibitors in the treatment of myoclonus,Tourette's syndrome, dystonia and tics is known in the literature.

In a specific aspect, a movement disorder also includes multiplesclerosis, basal ganglia disorders, hypokinesia, and dyskinesia.

Lewy Body Diseases

In one embodiment, the present embodiment, the invention provides amethod of treating a Lewy Body Disease, comprising administering to ananimal in need of such treatment an effective amount of a compound orcomposition of the present invention. Lewy bodies appear as sphericalmasses that displace other cell components. The two morphological typesare classical (brain stem) Lewy bodies and cortical Lewy bodies. Aclassical Lewy body is an eosinophilic cytoplasmic inclusion consistingof a dense core surrounded by a halo of 10-nm-wide radiating fibrils,the primary structural component of which is alpha-synuclein. Incontrast, a cortical Lewy body is less well defined and lacks the halo.Nonetheless, it is still made up of alpha-synuclein fibrils. CorticalLewy bodies are a distinguishing feature of Dementia with Lewy bodies(DLB), but may occasionally be seen in ballooned neurons characteristicof Pick's disease and corticobasal degeneration, as well as in patientswith other tauopathies.

More particularly, the Lewy Body disorder is selected from the groupconsisting of multiple system atrophy, particularly the Parkinsonianvariant; Parkinson disease without or with dementia (PDD); dementia withLBs (DLB) alone or in association with Alzheimer disease (AD); multiplesystem atrophy, particularly the Parkinsonian variant, as well as Pick'sdisease and corticobasal degeneration.

Multiple Sclerosis

In one embodiment, the present invention provides a method of treating amotor symptom associated with multiple sclerosis (MS), comprisingadministering to animal in need of such treatment an effective amount ofa compound or composition of the present invention. MS is an autoimmune,demyelinating disease that affects the brain and spinal cord of the CNS.It affects women more than men and is most commonly diagnosed betweenages 20 and 40, but can be seen at any age.

MS is caused by damage to the myelin sheath, the protective coveringthat surrounds nerve cells. When this nerve covering is damaged, nervesignals slow down or stop. Because nerves in any part of the brain orspinal cord may be damaged, patients with multiple sclerosis can havesymptoms in many parts of the body. Symptoms vary, because the locationand severity of each attack can be different. Episodes can last fordays, weeks, or months. These episodes alternate with periods of reducedor no symptoms (remissions).

Muscle symptoms associated with MS include loss of balance; musclespasms; numbness, tingling, or abnormal sensation in any area; problemsmoving arms or legs; problems walking; problems with coordination andmaking small movements; tremor in one or more arms or legs; and weaknessin one or more arms or legs.

Basal Ganglia Disorders

In particular embodiments, the present invention provides a method oftreating a basal ganglia disorder. Basal ganglia disorders refer to agroup of physical dysfunctions that occur when the group of nuclei inthe brain known as the basal ganglia fail to properly suppress unwantedmovements or to properly prime upper motor neuron circuits to initiatemotor function (Leisman and Mello, Rev. Neurosci. 2013, 24, 9-25).

Increased output of the basal ganglia inhibits thalamocorticalprojection neurons. Proper activation or deactivation of these neuronsis an integral component for proper movement. If something causes toomuch basal ganglia output, then the thalamocortical projection neuronsbecome too inhibited and one cannot initiate voluntary movement. Thesedisorders are known as hypokinetic disorders. However, a disorderleading to abnormally low output of the basal ganglia leads torelatively no inhibition of the thalamocortical projection neurons. Thissituation leads to an inability to suppress unwanted movements. Thesedisorders are known as hyperkinetic disorders (Wichmann and DeLong,Curr. Opin. Neurobiol 1996, 6, 751-758).

Hypokinesia

In particular embodiments, the present invention provides a method oftreating hypokinesia. Hypokinesia refers to decreased bodily movements,and they may be associated with basal ganglia diseases (such asParkinson's disease), mental health disorders and prolonged inactivitydue to illness, amongst other diseases.

More generally, hypokinesia describes a spectrum of disorders,including: (i) Akinesia, which refers to the inability to initiatemovement due to difficulty selecting or activating motor programs in thecentral nervous system. Akinesia is a result of severely diminisheddopaminergic cell activity in the direct pathway of movement and iscommon in severe cases of Parkinson's disease; (ii) Bradykinesia, whichis characterized by slowness of movement and has been linked toParkinson's disease and other disorders of the basal ganglia. Ratherthan being a slowness in initiation (akinesia), bradykinesia describes aslowness in the execution of movement. It is one of the 3 key symptomsof parkinsonism, which are bradykinesia, tremor and rigidity.Bradykinesia is also the cause of what is normally referred to as “stoneface” (expressionless face) among those with Parkinson's; (iii)Freezing, which is characterized by an inability to move muscles in anydesired direction; and (iv) Rigidity, which is characterized by anincrease in muscle tone causing resistance to externally imposed jointmovements; and (v) Postural instability, which is the loss of ability tomaintain an upright posture.

Dyskinesia

In particular embodiments, the present invention provides a method oftreating dyskinesia. Dyskinesia is a movement disorder which consists ofadverse effects including diminished voluntary movements and thepresence of involuntary movements, similar to tics or chorea.

Dyskinesia can be anything from a slight tremor of the hands touncontrollable movement of, most commonly, the upper body but can alsobe seen in the lower extremities. Discoordination can also occurinternally especially with the respiratory muscles and it often goesunrecognized. Dyskinesia is a symptom of several medical disorders,distinguished by the underlying cause and generally corresponding to oneof three types: acute dyskinesia, chronic (or tardive) dyskinesia, andnon-motor dyskinesia.

More specifically, a dyskinesia can include one or more the following:paroxysmal dyskinesias, e.g., primary and secondary paroxysmaldyskinesias; paroxysmal kinesigenic dyskinesias (PKD); paroxysmalnon-kinesigenic dyskinesias (PNKD); paroxysmal exercise-induced(exertion-induced) dyskinesias (PED); and paroxysmal hypnogenicdyskinesias (PHD).

Trauma-Related Disorders

In specific embodiments, the present invention provides a method oftreating a trauma-related disorder, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition of the present invention.

In specific embodiments, trauma-related disorders comprise brain trauma;head trauma (closed and penetrating); head injury; tumors, especiallycerebral tumors affecting the thalamic or temporal lobe head injuries;cerebrovascular disorders (diseases affecting the blood vessels in thebrain), such as stroke, ischemia, hypoxia, and viral infection (e.g.,encephalitis); excitotoxicity; and seizures.

Conditions within the scope of the invention that are amenable toneuroprotection include: Stroke; traumatic brain injury (TB); Dementia;Alzheimer's disease; Parkinson's disease; Huntington's disease; Cerebralpalsy; Post-polio syndrome; Guillain-Barre syndrome, and MultipleSclerosis; and other developmental syndromes, genetic conditions, andprogressive CNS diseases affecting cognitive function, such as autismspectrum disorders, fetal alcohol spectrum disorders (FASD),Rubinstein-Taybi syndrome, Down syndrome, and other forms of mentalretardation.

Pain Disorders

In specific embodiments, the invention provides methods of treatingpain, comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of PDE4 inhibitors in the treatment of pain is knownin the literature.

In particular embodiments, the pain disorder includes one or more of thefollowing: dental pain, cancer pain, myofascial pain, perioperativepain, acute pain, chronic pain, posttraumatic pain, trigeminalneuralgia, migraine severe pain, intractable pain, neuropathic pain,post-traumatic pain, cancer pain, non-cancer pain. Pain also encompassesa pain disorder associated with psychological factors, a pain disorderassociated with a general medical condition, and a pain disorderassociated with both psychological factors and a general medicalcondition.

Cognitive Disorders

In particular embodiments of the invention, the neurological disorder isa cognitive disorder. Accordingly, the present invention provides amethod of treating a cognitive disorder, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of cognitive disorders is known in theliterature (e.g., U.S. Pat. Nos. 7,829,713; 8,338,405).

Cognitive disorders can significantly impair social and occupationalfunctioning, adversely impacting the autonomy and quality of life of theaffected individual. An estimated four to five million Americans (about2% of all ages and 15% of those older than 65) have some form and degreeof cognitive impairment (Abrams et al., Merck Manual of Geriatrics,1995, Whitehouse Station (NJ), Medical Services).

Cognitive disorders reflect problems in cognition, i.e., the generalprocesses by which knowledge is acquired, retained and used.Accordingly, cognitive disorders can encompass impairments in suchfunctions as concentration, perception, attention, informationprocessing, learning, memory, or language. Cognitive disorders can alsoencompass impairments in psychomotor learning abilities, which includephysical skills, such as movement and coordination; fine motor skillssuch as the use of precision instruments or tools; and gross motorskills, such as dance, musical, or athletic performance.

Cognitive disorders also encompass impairments in executive functions,which include abilities underlying the planning and execution ofgoal-oriented behaviors. Such abilities include flexibility, i.e., thecapacity for quickly switching to the appropriate mental mode;anticipation and prediction based on pattern recognition; reasoning andproblem-solving; decision making; working memory, i.e., the capacity tohold and manipulate internally- or externally-derived information inreal time; emotional self-regulation, including the ability to recognizeand manage one's emotions for good performance; sequencing, such as theability to dissect complex actions into manageable units and prioritizethem in the right order; and self-inhibition, i.e., the ability towithstand distraction and internal urges.

Cognitive disorders also comprise cognitive impairments (deficits ordysfunctions) that are associated with (due to) to CNS disorders. In oneaspect, a cognitive impairment can be a direct result of a CNS disorder.For example, impairments in speech and language can directly result froma stroke or head-injury that damages the brain regions controllingspeech and language, as in aphasia.

In another aspect, a cognitive impairment is associated with a complexCNS disorder, condition, or disease. For example, a cognitive impairmentcan comprise a deficit in executive control that accompanies autism ormental retardation; a deficit in memory associated with schizophrenia orParkinson's disease; or a cognitive deficit arising from multiplesclerosis. In the case of multiple sclerosis (MS), for example, aboutone-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, or impairedmemory. Such problems typically occur later in the course of MS—althoughin some cases they can occur much earlier, if not at the onset ofdisease.

Cognitive impairments can be due to many, non-exclusive categories ofCNS disorders, including the following (and as described herein):

-   (1) dementias, such as those associated with Alzheimer's disease,    Parkinson's disease; Huntington's disease, Pick's disease,    Creutzfeldt-Jakob, AIDS Dementia, and other neurodegenerative    disorders; and cognitive disabilities associated with progressive    diseases involving the nervous system, such as multiple sclerosis.-   (2) psychiatric disorders, which include affective (mood) disorders,    such as depression and bipolar disorders; psychotic disorders, such    as schizophrenia and delusional disorder, and neurotic and anxiety    disorders, such as phobias, panic disorders, obsessive-compulsive    disorder, generalized anxiety disorder, eating disorders; and    posttraumatic stress disorders.-   (3) developmental syndromes, genetic conditions, and progressive CNS    diseases affecting cognitive function, such as autism spectrum    disorders; fetal alcohol spectrum disorders (FASD); Rubinstein-Taybi    syndrome; Down syndrome, and other forms of mental retardation; and    multiple sclerosis.-   (4) trauma-dependent losses of cognitive functions, i.e.,    impairments in memory, language, or motor skills resulting from    brain trauma; head trauma (closed and penetrating); head injury;    tumors, especially cerebral tumors affecting the thalamic or    temporal lobe; cerebrovascular disorders (diseases affecting the    blood vessels in the brain), such as stroke, ischemia, hypoxia, and    viral infection (e.g., encephalitis); excitotoxicity; and seizures.    Such trauma-dependent losses also encompass cognitive impairments    resulting from extrinsic agents such as alcohol use, long-term drug    use, and neurotoxins, e.g., lead, mercury, carbon monoxide, and    certain insecticides (e.g., Duncan et al., Drug Discover. Ther.    2012, 6, 112-122).-   (5) age-associated cognitive deficits, including age-associated    memory impairment (AAMI; also referred to herein as age-related    memory impairment (AMI)), and deficits affecting patients in early    stages of cognitive decline, as in Mild Cognitive Impairment (MCI);    and-   (6) learning, language, or reading disabilities, such as perceptual    handicaps, dyslexia, and attention deficit disorders.

Accordingly, the invention provides a method of treating a cognitiveimpairment associated with a CNS disorder selected from one or more ofthe group comprising: dementias, including those associated withneurodegenerative disorders; psychiatric disorders; developmentalsyndromes, genetic conditions, and progressive CNS diseases and geneticconditions; trauma-dependent losses of cognitive function,age-associated cognitive deficits; and learning, language, or readingdisorders.

Dementias

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with dementia, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Dementias are neurodegenerative diseases characterized by learning andcognitive deficiencies and are typically accompanied by behavioralsymptoms, psychological symptoms and motor symptoms. More particularly,dementia symptoms can include difficulty with many areas of mentalfunction, including emotional behavior or personality, language, memory,perception, and thinking and judgment.

Dementias include, but are not limited to, the following: dementia dueto Alzheimer's disease (with early or late onset), dementia due toParkinson's disease, dementia due to Pick's disease, dementia due toCreutzfeldt-Jakob disease, dementia due to HIV disease, dementia due tohead trauma; dementia due to a vascular disease (“vascular dementia”),Lewy body dementia, fronto-temporal dementia, Pick's disease andcorticobasal degeneration.

In one embodiment, dementia is due to Alzheimer's disease. Accordingly,the present invention provides a method of treating dementia due toAlzheimer's disease, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of PDE4inhibitors in the treatment of Alzheimer's disease is known in theliterature. Accordingly, the invention provides a method of treatingdementia due to Alzheimer's disease, comprising administering to ananimal in need of such treatment a therapeutically effective amount of acompound or pharmaceutical composition described herein.

In another embodiment, dementia is due to Parkinson's disease.Accordingly, the invention provides a method of treating dementia due toParkinson's disease, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. Dementia has been reportedto occur in approximately 20%-60% of individuals with Parkinson'sdisease and is more likely to be present in older individuals or thosewith more severe or advanced disease. The dementia associated withParkinson's disease is characterized by cognitive and motoric slowing;problems with executive functioning, such as planning tasks, organizingprojects, or carrying out goals in the proper sequence; and impairmentin memory retrieval. Declining cognitive performance in individuals withParkinson's disease is frequently exacerbated by depression. The utilityof PDE4 inhibitors in treating Parkinson's disease is known in theliterature.

Dementia has been reported to occur in approximately 20%-60% ofindividuals with Parkinson's disease and is more likely to be present inolder individuals or those with more severe or advanced disease. Thedementia associated with Parkinson's disease is characterized bycognitive and motoric slowing, executive dysfunction, and impairment inmemory retrieval. Declining cognitive performance in individuals withParkinson's disease is frequently exacerbated by depression. For areview, Davie, Br. Med. Bull. 2008, 86, 109-127. The motor symptoms ofParkinson's disease result from the death of dopamine-generating cellsin the substantia nigra, a region of the midbrain; the cause of thiscell death is unknown. Early in the course of the disease, the mostobvious symptoms are movement-related. Four motor symptoms areconsidered cardinal in PD: shaking (tremors), rigidity, slowness ofmovement, and postural instability, i.e., difficulty with walking andgait (e.g., Jankovic, J. Neurol. Neurosurg. Psychiatr. 2008, 79,368-376). Later, cognitive and behavioral problems may arise, withdementia commonly occurring in the advanced stages of the disease. Othersymptoms include sensory, sleep and emotional problems. PD is morecommon in the elderly, with most cases occurring after the age of 50.

In another aspect, a cognitive impairment is associated with a complexCNS syndrome, condition, or disease. For example, a cognitive impairmentcan comprise a deficit in executive control that accompanies autism ormental retardation; a deficit in memory associated with schizophrenia orParkinson's disease; or a cognitive deficit arising from multiplesclerosis. In the case of multiple sclerosis (MS), for example, aboutone-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, or impairedmemory. Such problems typically occur later in the course of MS—althoughin some cases they can occur much earlier, if not at the onset ofdisease.

In one aspect, a cognitive impairment can be a direct result of a CNSdisorder. For example, impairments in speech and language can directlyresult from a stroke or head-injury that damages the brain regionscontrolling speech and language, as in aphasia.

Psychiatric Disorders

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with a psychiatric disorder, comprisingadministering to an animal in need of such treatment an effective amountof a compound or pharmaceutical composition described herein.Psychiatric disorders include affective disorders (mood disorders), suchas depression and bipolar disorders; psychotic disorders, such asschizophrenia and delusional disorder, and neurotic and anxietydisorders, such as phobias, panic disorders, obsessive-compulsivedisorder, generalized anxiety disorder, eating disorders, andposttraumatic stress disorders.

Developmental Syndromes, Genetic Disorders, and Progressive Diseases

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with a developmental syndrome, geneticdisorder, or progressive disease, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In a specific aspect, thecognitive deficit is associated with an autism spectrum disorder; afetal alcohol spectrum disorder (FASD); Rubinstein-Taybi syndrome; Downsyndrome, and other forms of mental retardation; and multiple sclerosis.

Trauma-Related Disorders

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with trauma. Such trauma-dependent lossesof cognitive function include, but are not limited to, those due tocerebrovascular diseases, including stroke and ischemia; brain trauma,including subdural hematoma and brain tumor, traumatic brain injury(TBI) and head injury.

Such trauma-dependent losses also encompass cognitive impairmentsresulting from extrinsic agents such as alcohol use, long-term drug use,and neurotoxins such as lead, mercury, carbon monoxide, and certaininsecticides.

Stroke

In some embodiments, chemical entities and compositions of the presentinvention are useful in treating stroke, and in more specificembodiments, treating motor or cognitive impairments during post-strokerehabilitation. Stroke care is a temporal continuum that includesimmediate (acute) treatments and subsequent rehabilitative therapy.

Acute treatments directly target the initial damage, such as thattriggered by ischemic or hemorrhagic stroke; they usually involve usingagents to dissolve clots and restore blood flow to reduce tissue damageand stabilize the patient. The efficacy of acute treatments is typicallylimited to a short time window extending only a few hours from strokeonset.

Rehabilitation becomes the therapeutic focus after the patient has beenmedically stabilized. Rehabilitation (also referred to as “strokerehabilitation” or “post-stroke rehabilitation”) is directed tocognitive and motor deficits that persist after the initial strokeinjury, the goal being to restore and recover neurological function asmuch as possible to compensate for the permanent tissue loss. (e.g.,1995 Clinical Guideline by the Department of Health and Human Serviceson Post-Stroke Rehabilitation.)

Stroke rehabilitation is typically a comprehensive program coordinatedby a team of medical professionals. A physical therapist on the team,for example, may focus on maintaining and restoring range of motion andstrength in affected limbs, maximizing mobility in walking, improvingmanual dexterity, and rehabilitating other motor and sensorimotorfunctions. A mental health professional may be involved in the treatmentof loss of cognitive skills. Rehabilitation services can occur inmultiple environments, such as a rehabilitation hospital, long-term carefacility, outpatient clinic, or at home.

Neurological functions impacted by stroke (and which can be targetedduring rehabilitation) include impairments in cognitive and motorfunctions. Cognitive function impairments, for example, can manifest asdeficits in understanding speech or writing (aphasia); knowing the rightwords but having trouble saying them clearly (dysarthria); as well asdeficits in other cognitive functions, such as attention, reasoning,planning, execution, and learning and memory. Motor functionimpairments, for example, can manifest as weakness (hemiparesis) orparalysis (hemiplegia) on one side of the body that may affect the wholeside or just the arm or leg; by problems with balance or coordination;deficits in gross motor skills such as gait and walking speed; deficitsin fine motor skills or manual dexterity; and deficits in upper andlower extremity function.

Accordingly, the present invention provides the use of a PDE4 inhibitorin the treatment of stroke, including methods of post strokerehabilitation. In certain embodiments, chemical entities of the presentinvention are useful during stroke rehabilitation to treat strokedeficits (or “post-stroke deficits”) resulting from impairedneurological functions. In some embodiments, the present inventionprovides methods of post-stroke rehabilitation comprising: (a)administering to a subject in need thereof a PDE4 inhibitor duringrecovery of the subject from stroke; (b) providing training to thesubject under conditions sufficient to improve performance of aneurological function whose impairment is due to said stroke; and (c)repeating steps (a) and (b) one or more times, whereby the amount oftraining sufficient to improve the performance is reduced relative tothat produced by training alone.

In one aspect, the PDE4 inhibitor is a chemical entity of the presentinvention. In some embodiments, the deficit is a motor deficit. In otherembodiments, the deficit is a cognitive deficit, particularly, a deficitin memory formation, and more specifically, a deficit in long-termmemory formation. In still other embodiments, the deficit may include acognitive and motor deficit. In another aspect, training comprises abattery of tasks directed to the neurological function. In a specificaspect, the reduction in the amount of training is a reduction in thenumber of training sessions.

In a further embodiment, one or more training steps are separated by adiscrete interval. In one aspect, each training step is provided daily.In other aspects, the interval between one or more training steps can beless than one day or more than one day e.g., such as once a week, twicea week, three times a week, or longer.

In a further embodiment, said administering step (a) is in conjunctionwith said training step (b). In one aspect, the subject is a human. Inanother aspect, the subject has undergone neuronal stem cellmanipulation. In other aspects, the compound is administered before andduring each training session.

Age-Associated Cognitive Deficits AAMI

In a specific embodiment, the invention provides a method of treating anage-associated cognitive deficit. In one aspect, the age-associatedcognitive deficit is age-related memory impairment (AAMI). Accordingly,the invention provides a method of treating age-associated memoryimpairment (AAMI), comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein.

AAMI is a decline in various cognitive abilities, in particular memoryabilities, associated with normal aging. For example, AAMI subjects showa decline in the ability to encode new memories of events or facts, aswell as working memory (Hedden and Gabrieli, Nat. Rev. Neurosci. 2004,S, 87-96). In addition, AAMI subjects, when compared with age-matchedcontrols, appeared to be impaired in tests of executive functionsassociated with frontal lobe function. These and other studies suggestan important role for frontal lobe dysfunction in the memory loss ofelderly people. More generally, studies comparing the effects of agingon episodic memory, semantic memory, short-term memory and priming findthat episodic memory is especially impaired in normal aging; but sometypes of short-term memory can also be impaired (Nilsson, Acta Neurol.Scand. Suppl. 2003, 179, 7-13).

In general, an AAMI diagnosis identifies persons with subjectively andobjectively evidenced memory loss without cognitive decline impairedenough to warrant the diagnosis of dementia. According to criteriaestablished by the NIH working group (Crook et al., Devel. Neuropsychol.1986, 2, 261-276) a diagnosis of AAMI includes the following in a personaged 50 or older:

-   -   (i) the presence of subjective memory decline, e.g., complaints        of memory loss reflected in such everyday problems as difficulty        remembering names of individuals introduced to the subject,        misplacing objects, difficulty remembering a list of items to be        purchased or a list of tasks to be performed;    -   (ii) objective evidence of memory loss (e.g., a score at least        one standard deviation below the mean of younger adults in a        well standardized memory test);    -   (iii) evidence of adequate intellectual function (e.g., a raw        score of at least 32) on the Vocabulary subtest of the Wechsler        Adult Intelligence Scale; and    -   (iv) the absence of dementia (or other memory-affecting disease,        such as stroke), e.g., based on the Global Deterioration Scale        for assessment of dementia, individuals with AAMI have very mild        cognitive decline (level 2) (Reisberg et al., Am. J. Psych.        1982, 139, 1136-1139).

Individuals with AAMI have been shown to have a three-fold greater riskfor development of dementia than individuals who do not meet AAMIcriteria (Goldman and Morris, Alzheimer Dis. Assoc. Disord. 2002,15:72-79).

MCI

In a specific embodiment, the invention provides a method of treatingmild cognitive impairment (MCI), comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

MCI may be diagnosed when an individual's memory declines below thelevel considered normal for that age group. In other words, MCI is acondition in which people face memory problems more often than that ofthe average person their age. These symptoms, however, do not preventthem from carrying out normal activities and are not as severe as thesymptoms for Alzheimer's disease. Symptoms often include misplacingitems, forgetting events or appointments, and having trouble thinking ofdesired words.

According to recent research, MCI has been called the transitional statebetween cognitive changes of normal aging and Alzheimer's disease (AD).Many people who experience mild cognitive impairment are at a high riskof developing Alzheimer's disease. Indeed, research suggests that: about12% of people aged 65 or older diagnosed with MCI go on to developAlzheimer's disease within a year; and that about 40% developAlzheimer's within three years. This is a much higher rate than in thegeneral population, wherein only about 1% of people aged 65 or olderdevelop Alzheimer's each year.

Thus, people with MCI are considered at heightened risk to developAlzheimer's disease. These symptoms, however, do not prevent them fromcarrying out normal activities and are not as severe as the symptoms forAlzheimer's disease. Symptoms often include misplacing items, forgettingevents or appointments, and having trouble thinking of desired words(e.g., Arnáiz and Almkvist, Acta Neurol. Scand. Suppl. 2003, 179,34-41). Some patients with MCI, however, never progress to AD.

Learning and Related Disabilities

In a specific embodiment, the invention provides a method of treating alearning, language, or reading disability, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Neuroprotection

In specific embodiments, the invention provides a method ofneuroprotection, comprising administering to animal in need thereof aneffective amount of a chemical entity or composition of the presentinvention.

Like neuroplasticity, neuroprotection reflects an endogenousneurobiological process that is central to protection of the nervoussystem. More specifically, neuroprotection refers to the ability to haltor slow the loss of neurons, thereby preventing or slowing diseaseprogression and secondary injuries. In a particular aspect,neuroprotection targets neuronal damage arising from oxidative stressand excitotoxicity—both of which are highly associated with CNSdisorders, despite differences in symptoms or injuries.

The utility of PDE4 inhibitors in the treatment of neuronal damage isknown in the literature. In addition to neurodegenerative diseases,neuronal damage can also result from other sources of trauma, such ascerebrovascular diseases, including stroke and ischemia; brain trauma,including subdural hematoma and brain tumor; and head injury.

Augmented Cognitive and Motor Training

In certain embodiments, a compound or composition herein is used as anaugmenting agent in methods to enhance the efficiency of cognitive ormotor training (collectively “training”). Such enhancement methods arecollectively known as “augmented training,” comprising “augmentedcognitive training” or “augmented motor training.”

Training generally requires multiple sessions to attain the desiredbenefits, for example, to rehabilitate a motor deficit or languagedeficit following stroke. This can be costly and time-consuming,deterring subject compliance and the realization of real world benefitsthat endure over time. The efficiency of such training protocols can beimproved by administering certain agents (known as augmenting agents) inconjunction with the training protocol (e.g., U.S. Pat. Nos. 7,868,015;7,947,731; US 2008-0188525). Augmented training comprises a specifictraining protocol for a particular brain function, such as thatunderlying declarative memory, performance of a fine motor skill,locomotion, language acquisition, an executive function, etc., and ageneral administration of CREB pathway-enhancing drugs. The trainingprotocol (cognitive or motor training) induces neuronal activity inspecific brain regions and produces improved performance of a specificbrain (cognitive or motor) function. In other words, the use ofaugmenting agents achieves cognitive training effects with lessrepetition, i.e., fewer training sessions.

In some embodiments, the invention provides methods of treating acognitive disorder, and more particularly, methods for improving acognitive deficit associated with a central nervous system (CNS)disorder or condition in an animal, comprising treating the animal withan augmenting agent that enhances CREB pathway function in conjunctionwith cognitive training, wherein the augmenting agent is a compound orcomposition of the present invention. Exemplary compounds of the presentinventions, for example, have been shown to activate CREB in cell-basedassays.

In one aspect, the method comprises: (a) providing cognitive training toa subject in need of treatment of a cognitive deficit under conditionssufficient to produce an improvement in performance by said animal of acognitive function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said cognitive training;repeating steps (a) and (b) one or more times; and (d) reducing thenumber of training sessions sufficient to produce the improvement inperformance, relative to the same improvement in performance produced bycognitive training alone.

In another aspect, the method comprises: (a) providing cognitivetraining to a subject in need of treatment of a cognitive deficit underconditions sufficient to produce an improvement in performance by saidanimal of a cognitive function whose impairment is associated with saidcognitive deficit; (b) administering a compound or composition of thepresent invention to the animal in conjunction with said cognitivetraining; repeating steps (a) and (b) one or more times; and (d)producing a long-lasting improvement in performance of said functionrelative to the improvement in performance of said function produced bycognitive training alone.

In one aspect, a compound or composition of the present invention can beused as an augmenting agent in conjunction with any psychotherapeuticapproach intended to modulate cognitive function in the brain, therebyenhancing the efficacy of such therapy by reducing the number ofsessions necessary to attain benefits.

In another aspect, the cognitive deficit treated by these methods is orincludes memory impairment, and more particularly, a defect in long-termmemory. Long-term memory (LTM) generally comprises two main biologicalproperties. First, formation of long-term memory requires synthesis ofnew proteins. Second, it involves cAMP-responsive transcription and ismediated through the cAMP-response element binding protein (CREB) familytranscription factors. Compounds of the present invention can act asCREB-augmenting agents and are therefore useful in enhancing memoryformation in an animal, and more particularly, transcription-dependentmemory. Indeed, exemplary compounds of the present invention activateCREB in cell-based assays.

In some embodiments, the invention provides methods of treating a motordisorder, and more particularly, methods for improving a motor deficitassociated with a central nervous system (CNS) disorder or condition inan animal comprising treating the animal with an augmenting agent thatenhances CREB pathway function in conjunction with motor training.Methods are also provided herein for providing sustained improvement ina motor deficit associated with a central nervous system (CNS) disorderor condition in an animal in need of said treatment comprisingadministering to the animal a compound or composition of the presentinvention; and detecting said sustained improvement.

In one aspect, the method comprises: (a) providing motor training to asubject in need of treatment of a motor deficit under conditionssufficient to produce an improvement in performance by said animal of amotor function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said motor training;repeating steps (a) and (b) one or more times; and (d) reducing thenumber of training sessions sufficient to produce the improvement inperformance, relative to the same improvement in performance produced bymotor training alone.

In another aspect, the method comprises: (a) providing motor training toa subject in need of treatment of a motor deficit under conditionssufficient to produce an improvement in performance by said animal of amotor function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said motor training;repeating steps (a) and (b) one or more times; and (d) producing along-lasting improvement in performance of said function relative to theimprovement in performance of said function produced by motor trainingalone.

In other embodiments, the invention provides methods for enhancing aspecific aspect of cognitive performance in an otherwise healthy animal(particularly in a human or other mammal or vertebrate) comprising (a)administering to the animal an augmenting agent of the presentinvention; and (b) training the animal under conditions sufficient toproduce an improvement in performance of a particular cognitive task bythe animal. In other embodiments, the present invention provides methodsof enhancing cognitive or motor performance, as well as methods forrepeated stimulation of neuronal activity or a pattern of neuronalactivity, such as that underlying a specific neuronal circuit(s).

Augmenting Agents

Augmenting agents, including the compounds and compositions herein, areable to enhance CREB pathway function. By enhancing CREB pathwayfunction in conjunction with training, such augmented training candecrease the number of training sessions required to improve performanceof a cognitive or motor function, relative to the improvement observedby training alone (e.g., U.S. 2007-0203154, U.S. 2011-0160248, U.S.2010-0317648, and U.S. Pat. No. 8,222,243).

The augmenting agent can be administered before, during or after one ormore of the training sessions. In a particular embodiment, theaugmenting agent is administered before and during each trainingsession. Treatment with an augmenting agent in connection with eachtraining session is also referred to as the “augmenting treatment”.

Training Protocols

Training protocols are generally employed in rehabilitating individualswho have some form and degree of cognitive or motor dysfunction. Forexample, training protocols are commonly employed in strokerehabilitation and in age-related memory loss rehabilitation. Becausemultiple training sessions are often required before an improvement orenhancement of a specific aspect of cognitive (or motor) performance(ability or function) is obtained in the individuals, training protocolsare often very costly and time-consuming. Augmented training methods aremore efficacious and therefore more cost-effective.

For example, human brain injury often results in motor and cognitiveimpairments. While advances in critical care medicine and patientmanagement have led to improvements in patient outcome followingtraumatic brain injury (TBI), there is currently no known treatment toprevent the neuronal cell death and dysfunction that follows TBI.Although multiple treatments have proven neuroprotective in pre-clinicalmodels of TBI, most have failed to show efficacy in humans.

Once a patient is stabilized following TBI, the standard of caredictates extensive motor or cognitive rehabilitation. During thisrehabilitation the patient often regains lost skills, finally resultingin improved functional outcome. It would be beneficial if pharmaceuticaltreatments could be developed to enhance motor or cognitiverehabilitation following TBI, and thus improve functional outcome.

Cognitive and motor training protocols and the underlying principles arewell known in the art (e.g., Allen et al., Parkinsons Dis. 2012, 1-15;Jaeggi et al., Proc. Natl. Acad. Sci. USA 2011, 108, 10081-10086; Cheinet al., Psychon. Bull. Rev. 2010, 17, 193-199; Klingberg, Trends Cogn.Sci. 2010, 14, 317-324; Owen et al., Nature 2010, 465, 775-778; Tsao etal., J. Pain 2010, 11, 1120-1128; Lustig et al., Neuropsychol. Rev.2009, 19, 504-522; Park and Reuter-Lorenz, Ann. Rev. Psych. 2009, 60,173-196; Oujamaa et al., Ann. Phys. Rehabil. Med. 2009, 52, 269-293;Frazzitta et al., Movement Disorders 2009, 8, 1139-1143; Jaeggi et al.,Proc. Natl. Acad. Sci. USA 2008, 105, 6829-6833; Volpe et al.,Neurorehabil. Neural Repair 2008, 22, 305-310; Fischer et al., Top.Stroke Rehab. 2007, 14, 1-12; Jonsdottir et al., Neurorehabil. NeuralRepair 2007, 21, 191-194; Stewart et al., J. Neurol. Sci. 2006, 244,89-95; Krakauer, Curr. Opin. Neurol. 2006, 19, 84-90; Belleville et al.,Dement. Geriatr. Cogn. Disord. 2006, 22, 486-499; Klingberg et al., J.Am. Acad. Child Adolesc. Psychiatry 2005, 44, 177-186; Dean et al.,Arch. Phys. Med. Rehabil. 2000, 81, 409-417; Whitall et al., Stroke2000, 31, 2390-2395; Hummelsheim and Eickhof, Scand. J. Rehabil. Med.1999, 31, 250-256; Merzenich et al., Science 1996, 271, 77-81; Merzenichet al., Cold Spring Harb. Symp. Quant. Biol. 1996, 61, 1-8; Rider andAbdulahad, Percept. Mot. Skills 1991, 73, 219-224; Wek and Husak,Percept. Mot. Skills, 1989, 68, 107-113.

Cognitive training protocols are directed to numerous cognitivedimensions, including memory, concentration and attention, perception,learning, planning, sequencing, and judgment. Motor training protocolscan be directed to numerous motor domains, such as the rehabilitation ofarm or leg function after a stroke or head injury. One or more protocols(or modules) underling a training program can be provided to a subject.

In some embodiments, the protocols can be used to treat, orrehabilitate, cognitive or motor impairments in afflicted subjects. Suchprotocols may be restorative or remedial, intended to reestablish priorskills and functions, or they may be focused on delaying or slowingcognitive or motor decline due to neurological disease. Other protocolsmay be compensatory, providing a means to adapt to a cognitive or motordeficit by enhancing function of related and uninvolved brain domains.In other embodiments, the protocols can be used to improve particularskills or cognitive or motor functions in otherwise healthy individuals.For example, a cognitive training program might include modules focusedon delaying or preventing cognitive decline that normally accompaniesaging; here the program is designed to maintain or improve cognitivehealth.

In general, a training protocol (or module) comprises a set of distinctexercises that can be process-specific or skill-based: Process-specifictraining focuses on improving a particular domain such as attention,memory, language, executive function, or motor function. Here the goalof training is to obtain a general improvement that transfers from thetrained activities to untrained activities associated with the samecognitive or motor function or domain. For example, an auditorycognitive training protocol can be used to treat a student with impairedauditory attention. At the end of training, the student should show ageneralized improvement in auditory attention, manifested by anincreased ability to attend to and concentrate on verbal informationpresented in class—and therefore to remember to write down and completehomework assignments. Similarly, a cognitive training protocol may bedirected to impaired executive function in an autistic subject,preventing the subject from carrying out instructions to complete anactivity, such as making a meal, cleaning one's room, or preparing forschool in the morning. Cognitive training allows the subject to focushis attention and concentration and as a result, complete the sequenceof tasks required for such activities.

Skill-based training is aimed at improving performance of a particularactivity or ability. Here the goal of training is to obtain a generalimprovement in the skill or ability. For example, a training protocolmay focus on learning a new language, performing a musical instrument,improving memory, or learning a fine motor skill. The differentexercises within such a protocol will focus on core componentsunderlying the skill. Modules for increasing memory, for example, mayinclude tasks directed to the recognition and use of fact, and theacquisition and comprehension of explicit knowledge rules.

Some rehabilitation programs may rely on a single strategy (such ascomputer-assisted cognitive training) targeting either an isolatedcognitive function or multiple functions concurrently. For example, theCogState testing method comprises a customizable range of computerizedcognitive tasks able to measure baseline and change in cognitive domainsunderlying attention, memory, executive function, as well as languageand social-emotional cognition (e.g., Yoshida et al., PloS ON, 2011, 6,e20469; Frederickson et al., Neuroepidemiology 2010, 34, 65-75). Otherrehabilitation programs may use an integrated or interdisciplinaryapproach. Cognitive and motor training programs may involve computergames, handheld game devices, interactive exercises, and may employfeedback and adaptive models.

Neurorehabilitation and Neurorecovery

In other embodiments, the invention further relates to the use ofcompounds and compositions of the present invention in neurorecovery andneurorehabilitation—endogenous neurobiological processes that arecentral to recovery of cognitive and motor impairments of the nervoussystem (e.g., Harkema et al., Arch. Phys. Med. Rehabil. 2012, 93,1588-1597; Muresanu et al., J. Cell. Mol. Med. 2012, 16, 2861-2871).

Neurorehabilitation or neurorecovery generally refers to a collectionprocess that focuses on aiding a person's recovery from a neurologicaldisorder, or helping that individual to live a more normal, active, andindependent life. For example, the quality of life of a person can begreatly affected by a brain or spinal cord injury, or a medicalcondition which affects the mobility, cognitive functions, or otherphysical or psychological processes that have been affected by changesin the nervous system. The goal of neurorehabilitation is to combatthose changes and improve quality of life by various therapies.

Conditions within the scope of the invention that are treated byneurorehabilitation and neurorecovery include: Stroke; traumatic braininjury (TB); Dementia; Alzheimer's disease; Parkinson's disease;Huntington's disease; Cerebral palsy; Post-polio syndrome;Guillain-Barre syndrome, and Multiple Sclerosis; and other developmentalsyndromes, genetic conditions, and progressive CNS diseases affectingcognitive function, such as autism spectrum disorders, fetal alcoholspectrum disorders (FASD), Rubinstein-Taybi syndrome, Down syndrome, andother forms of mental retardation.

By focusing on all aspects of a person's well-being, neurorehabilitationor neurorecovery offers a series of therapies from the psychological tooccupational, teaching or re-training patients on mobility skills,communication processes, and other aspects of that person's dailyroutine. Neurorehabilitation or neurorecovery also provides focuses onnutrition, psychological, and creative parts of a person's recovery.

In one embodiment, the present invention provides a method of augmentingneurorehabilitation or neurorecovery from a cognitive impairment,comprising (a) providing cognitive training to a subject in need oftreatment of a cognitive deficit under conditions sufficient to producean improvement in performance by said animal of a cognitive functionwhose impairment is associated with said cognitive deficit; (b)administering a compound or composition of the present invention to theanimal in conjunction with said cognitive training; repeating steps (a)and (b) one or more times; and (d) producing a long-lasting improvementin performance of said function relative to the improvement inperformance of said function produced by cognitive training alone.

In another embodiment, the present invention provides a method ofaugmenting neurorehabilitation or neurorecovery from a motor impairment,comprising: (a) providing motor training to a subject in need oftreatment of a motor deficit under conditions sufficient to produce animprovement in performance by said animal of a motor function whoseimpairment is associated with said cognitive deficit; (b) administeringa compound or composition of the present invention to the animal inconjunction with said motor training; repeating steps (a) and (b) one ormore times; and (d) reducing the number of training sessions sufficientto produce the improvement in performance, relative to the sameimprovement in performance produced by motor training alone.

Non-Human Animal Training Protocols

Aside from applications for humans, compounds and compositions of thepresent invention have additional uses for non-human animals, namely inenhancing (augmenting) the efficiency of training protocols directed tonumerous cognitive and motor functions.

Conditions, under which non-human animals would benefit, includeenhanced (augmented) training procedures for specific purposes, (e.g.hunting dogs, guide dogs, police dogs etc, or animals used in movieindustry).

Enhanced training protocols can also benefit animals that have beenexposed to stressful or traumatic conditions and are in need of trainingto treat the resulting cognitive impairments. Such a need may arise, forexample, after such an animal has been captured or transported,subjected to new housing conditions (as in a change of domicile orowner), or has developed analogous disorders and is distressed oraggressive, or displays stereotypic behavior, obsessive-compulsivebehavior, or anxiety. Animals which are subject to stress would alsoinclude animals used in racing (eg. dogs, horses, camels) or othersports, performing animals (such as circus animals and those appearingon stage, television or in the movies) and horses that perform dressageand other highly disciplined routines.

Compounds of the present invention can also enhance the efficiency ofrehabilitative protocols following physical injury to a non-humananimal, such as limb amputation. For example, administering anaugmenting agent of the present invention in conjunction with a trainingprotocol can increase the efficiency of a rehabilitative program bydecreasing the number of training sessions necessary to achieve animprovement in motor function.

In particular embodiments, compounds and compositions of the presentinvention are used in methods of training service animals. By combiningaugmenting agents of the present invention with training protocols, theefficiency of training non-human animals for service in both the publicand private sectors will be enhanced. Service animals are typicallydogs. However, other non-human animals can also be trained to performservices, such as assisting blind or disabled people. For example,miniature horses can be trained to guide the blind, to pull wheelchairs,or to provide support for Parkinson's patients. As another example,capuchin monkeys can be trained to assist disabled perform manual tasks,such as grasping items, operating knobs and switches, turning the pagesof a book.

In specific embodiments, augmented training with compounds andcompositions of the present invention can be used to reduce the numberof training sessions necessary to teach an animal skills that are usefulin public service, such as in law enforcement. In dogs, for example,such skills include, but are not limited to, the following: (i) publicorder maintenance, e.g., chasing, holding, or detaining suspects; (ii)search and rescue, e.g., locating suspects, missing persons, or objects;and (iii) contraband detection, e.g., detecting illicit substances suchas drugs, narcotics, explosives, weapons, and even human remains. Suchmethods can therefore be applied to police dogs, bomb-sniffing dogs,drug-sniffing dogs, search and rescue dogs, etc.

In other embodiments, augmented training (with compounds andcompositions of the present invention) can be used to reduce the numberof training sessions required to teach animals skills that are useful inthe private sector, such as security and medical care. In dogs, forexample, such skills can include, but are not limited to, the following:(i) private security, e.g., guarding property or protecting anindividual; (ii) handicap assistance, e.g., providing eyes for thevisually impaired, ears for the hearing-impaired, arms and legs for thephysically-disabled; (iii) health care, e.g., detecting cancer oraltering a caregiver to seizures in a subject; (iv) psychiatricassistance, e.g., calming a phobic person under stress-triggeringconditions, or alerting an autistic person to distracting repetitivemovements such as hand flapping; and (v) pest control, e.g., identifyingsource of infestations by bedbugs or termites.

In some embodiments, the training protocol can be directed to a singleskill or task, such as the detection of a single drug. In otherembodiments, the training protocol can be directed to a complex set ofskills, such as those underlying search and rescue. For a complex set ofskills, training will therefore comprise more than one task.

In another aspect, when training is carried out with a wide enough scopeof tasks, a generalized “rehabilitation” effect is expected, resultingin generalized improved function of one or more cognitive domains. Thisresults in improved performance of the animal of related tasks(involving the same cognitive domains) that are not specifically part ofthe training protocol.

Accordingly, the present invention provides a method of reducing thetime necessary to teach an animal one or more skills, wherein saidreducing comprising: a) administering an augmenting agent of the presentinvention to the animal; b) providing a training protocol to said dogunder conditions to improve performance of one or more tasks, whereinsaid training protocol comprises multiple training sessions; and c)decreasing the number of training sessions required to improveperformance of said one or more tasks relative to the number of saidtraining sessions required to produce said improvement in performance bythe training protocol alone.

The training protocol can be provided to the animal under conditions toimprove performance of a single task; a complex set of tasks; or a widescope of tasks, resulting in generalized improved function of one ormore cognitive domains. The tasks can relate to a skill involved inpublic service, such as public order maintenance, search and rescue, andcontraband detection. The tasks can also relate to a skill involved inprivate service, such as private security, handicap assistance, healthcare, psychiatric assistance, and pest control.

Peripheral Disorders

PDE4 enzymes are located in a number of peripheral tissues. For example,one or several PDE4D isoforms are expressed throughout most tissuestested, including cortex, hippocampus, cerebellum, heart, liver, kidney,lung and testis (Richter et al., Biochem. J., 2005, 388, 803-811). Thelocalization and regulation of PDE4D isoforms is thought to allow fortight and local regulation of cAMP levels, possibly limiting signalpropagation in specific subcellular compartments.

Thus, in one embodiment, the invention provides a method of treating aperipheral disorder associated with PDE4, by administering to an animalin need thereof a therapeutically effective amount of a compound orpharmaceutical composition described herein.

The peripheral disorder may include, but is not limited to, suchPDE4-associated disorders as inflammatory bowel disease (Banner andTrevethick, 2004, Trends Pharmacol. Sci. 25, 430-436); rheumatoidarthritis (Kobayashi et al., 2007, Mediators Inflamm. 2007, 58901);chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis,pulmonary artery hypertension (DeFranceschi et al., 2008, FASEB J., 22,1849-1860); renal diseases (Conti et al., 2003, J. Biol. Chem., 278,5493); allergic skin diseases and psoriasis (Baumer et al., 2007,Inflamm. Allergy Drug Targets, 6, 17-26).

EXAMPLES

The present disclosure will be further illustrated by the followingnon-limiting Examples. These Examples are understood to be exemplaryonly, and they are not to be construed as limiting the scope of theinvention herein, and as defined by the appended claims.

Preparative Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

Synthetic Schemes

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between −78° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

According to Scheme A, commercially available or syntheticallyaccessible 3-bromo-5-methylpyridin-2-ol (II) is difluoromethylated with2,2-difluoro-2-(fluorosulfonyl)acetic acid or the silyl ester of2-fluorosulfonyldifluoroacetate, preferably2,2-difluoro-2-(fluorosulfonyl)acetic acid, in an aprotic solvent, suchas ACN, a base, such as Na₂CO₃, NaH, and the like, preferably Na₂CO₃, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, preferably room temperature, to afford a compound offormula (VI) where Z is CH and R₄ is CHF₂ (Chen et al., J. FluorineChem., 1989, 44, 433-440).

According to Scheme A, a compound of formula (VI), where Z is CH, U is—CH₃, R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl, is prepared from acommercially available or synthetically accessible compound of formula(III), where U is —CH₃. Reaction of 3-bromo-2-chloro-5-methylpyridine,with an alkoxide, such as sodium ethoxide, sodium methoxide and thelike, in a suitable solvent, such as the alcohol used to generate thealkoxide, at a temperature ranging from room temperature to the refluxtemperature of the solvent, for a period of 4 to 48 h provides abromopyridyl ether compound of formula (VI). Alternatively, a compoundof formula (VI), where R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl, may beprepared by reaction of 3-bromo-2-chloro-5-methylpyridine with asuitably substituted primary or secondary alcohol, in the presence of abase such as NaH, in a solvent, such as DMA, 1,4-dioxane, THF, and thelike, at temperatures ranging from room temperature to the refluxtemperature of the solvent.

According to Scheme A, a compound of formula (VI), where Z is CH, U is—CH₂OH, R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl, is prepared in two stepsfrom a commercially available or synthetically accessible compound offormula (III), where U is —CO₂H or —CO₂C₁₋₃alkyl. For example,5-bromo-6-chloronicotinic acid is reacted with a suitably substitutedalcohol, in the presence of a base such as NaH, Cs₂CO₃, and the like,with our without a solvent, such as DMA, 1,4-dioxane, THF, and the like,at temperatures ranging from room temperature to the reflux temperatureof the solvent, employing conventional or microwave heating, for aperiod of 30 minutes to 8 h, to provide a compound of formula (VI),where R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl. In an alternate method, acompound of formula (VI), where U is —CO₂C₁₋₃alkyl, and R⁴ is —C₁₋₃alkylor —C₁₋₃haloalkyl, is prepared from a compound of formula (III), where Uis —CO₂H, where the acid is activated, with a suitable activating agent,followed by reaction with a suitable alcohol. For example5-bromo-6-chloronicotinic acid is reacted with a chlorinating agent suchas oxalyl chloride, in a solvent such as DMF, to provide the acidchloride. Subsequent reaction with an alkoxide, in a suitable solvent,such as the alcohol used to generate the alkoxide, provides a compoundof formula (VI), where U is —CO₂C₁₋₃alkyl, and R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl. In a subsequent reaction, a compound of formula (VI), where Uis —CO₂C₁₋₃alkyl, and R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl, is reducedwith a reducing agent such as NaBH₄, LiBH₄, or a mixture thereof, in asolvent such as THF, and the like, at temperatures ranging from 0° C. tort, to provide a compound of formula (VI), where U is —CH₂OH.

According to Scheme A, a compound of formula (VI), where Z is CH, U is—CH₂Cl, and R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl is prepared from acompound of formula (VI), where Z is CH, U is —CH₂OH, and R⁴ is—C₁₋₃alkyl or —C₁₋₃haloalkyl. For example(5-bromo-6-ethoxypyridin-3-yl)methanol is reacted with a halogenatingagent such as thionyl chloride, in a solvent such as DCM, and the like,at temperatures ranging from 0° C. to rt, to provide3-bromo-5-(chloromethyl)-2-ethoxypyridine.

A compound of formula (VI), where Z is CH, U is —CH(═O), and R⁴ is—C₁₋₃alkyl or —C₁₋₃haloalky, for example5-bromo-6-methoxynicotinaldehyde, is prepared from6-methoxynicotinaldehyde, employing a bromination reaction conditionsknown to one skilled in the art. For example, 6-methoxynicotinaldehydeis reacted with Br₂, NaOAc, in a solvent such as HOAc, at temperaturesranging from rt to 90° C., to provide 5-bromo-6-methoxynicotinaldehyde.

According to Scheme A, commercially available or syntheticallyaccessible 5-methylpyrazin-2-amine (IV), where R¹ is H, U is CH₃, and Zis N, is brominated under conditions known to one skilled in the art,for example, by reaction with a suitable halogenating agent such as NBS,Br₂, and the like, in an appropriate solvent such as DCM, 1,4-dioxane,THF, CHCl₃, preferably DCM, at temperatures ranging from 0° C. to roomtemperature, for a period of 8 to 16 h to afford3-bromo-5-methylpyrazin-2-amine. Subsequent reaction of3-bromo-5-methylpyrazin-2-amine (V) with an oxidizing agent, such as,but not limited to, tert-butyl nitrite, in the presence of an anhydrousacid source, for example, HCl in 1,4-dioxane, in an alcoholic solventsuch as MeOH, EtOH, and the like, at temperatures ranging from 0° C. to60° C., for a period of 8 to 16 h affords compounds of formula (VI),where Z is N, U is —CH₃, and R₄ is —C₁₋₃alkyl.

According to Scheme A, commercially available or syntheticallyaccessible 6-amino-2-methylnicotinonitrile (IV), where R¹ is —CH₃, U is—CN, and Z is CH is prepared in two steps (bromination anddiazotization/alcohol addition) by the methods previously described toprovide compounds of formula (VI) where R¹ is —CH₃, U is —CN, and Z isCH.

According to Scheme B,2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine(IX) is obtained in 2 steps from commercially available4-bromo-2-hydroxypyridine (VII). Alkylation of 4-bromo-2-hydroxypyridine(VII), with 2-chloro-2,2-difluoroacetate in a solvent such as ACN, THF,1,4-dioxane, or a mixture thereof, at temperatures ranging from roomtemperature to the reflux temperature of the solvent, for a period of6-12 h (also described in WO2010/056195, May 20, 2010) provides4-bromo-2-(difluoromethoxy)pyridine (VIII). A boronate ester is preparedusing methods known to one skilled in the art, for example,2-difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(IX) is prepared from 4-bromo-2-(difluoromethoxy)pyridine (VIII) byreaction with KOAc, K₃PO₄, and the like, a catalyst such as Pd(dppf)Cl₂,Pd(PPh₃)₄, and the like, bis(pinacolato)diboron, and the like, in asolvent such as 1,4-dioxane, 1-2-dimethoxyethane, DMF, DMSO, and thelike, at temperatures ranging from 60 to 150° C., for a period of 6-24h.

As shown in Scheme C, a compound of formula (VI), where U is —CH₃, —CN,—CH₂OH, —CH(═O), or —NH₂, Z is CH or N; R¹ is H or —CH₃, and R⁴ is—C₁₋₃alkyl or —C₁₋₃haloalkyl; under Suzuki reaction conditions known toone skilled in the art, is reacted with commercially available orsynthetically accessible aromatic or heteroaromatic boronic acids oresters, or synthetically accessible heteroaromatic boronic esters, suchas compound (IX), in a solvent such as ACN, toluene, EtOH, H₂O, or amixture thereof, in the presence of a base such as, NaHCO₃, Na₂CO₃,K₂CO₃, Cs₂CO₃, and the like, and a palladium catalyst such as Pd(dppf)₂,Pd(PPh₃)₄, and the like, employing conventional or microwave heating, attemperatures ranging from 80 to 120° C., to provide a compound offormula (X). A compound of formula (X) where R³ is aryl or heteroaryloptionally substituted with —OH, under standard alkylating conditionsknown to one skilled in the art, is treated with commercially availableor synthetically accessible alkyl groups with appropriate leavinggroups, such as halides, for example —Cl, —Br or —I, or sulfonates, suchas methanesulfonyl, p-toluenesulfonyl and the like, in the presence of abase, such as but not limited to, NaH, K₂CO₃, Cs₂CO₃, and the like, in asolvent such as DMF, DMSO, 1,-4-dioxane, and the like, at temperaturesranging from 60° C. to the reflux temperature of the solvent for aperiod of 8 to 24 h, to provide a aryl or heteroaryl O-alkyl compound offormula (X).

Halogenation of a compound of formula (X), where U is —CH₃ or —CH₂OH, Zis CH or N; R¹ is H or —CH₃, R₃ is aryl or heteroaryl, and R⁴ is—C₁₋₃alkyl or —C₁₋₃haloalkyl, under free-radical halogenationconditions. For example, a compound of formula (X), where U is —CH₃, isreacted with NBS, a radical initiator such as AIBN or benzoyl peroxide,in a solvent such as CCl₄, at temperatures ranging from 60° C. to thereflux temperature of the solvent, for a period of 4 to 24 h, provides acompound of formula (XI), where HAL is —Br. In an alternate method, acompound of formula (X), where U is —CH₂OH, is reacted with achlorinating agent such as thionyl chloride, employing methodspreviously described, to provide a compound of formula (X), where HAL is—Cl.

A nitrile compound of formula (X), where U is —CN, Z is CH; R¹ is —CH₃,R₃ is aryl or heteroaryl, and R⁴ is —CH₃, is reduced to thecorresponding aldehyde with a reducing agent such as DIBAL, and thelike, in a solvent such as DCM, THF, toluene, and the like, at lowtemperature, preferably −78° C., for a period of 1 to 3 h. Subsequentreduction of the aldehyde moiety to the corresponding alcohol, isaccomplished with a reducing agent, such as sodium or lithiumborohydride, and the like, in a solvent such as MeOH, THF, and the like,at temperatures ranging from 0° C. to room temperature. Activation ofthe alcohol using methanesulfonyl chloride, in a suitable solvent, suchas DCM, in the presence of an alkylamine base, such as Hünig's base,TEA, and the like, provides a compound of formula (XI), where U is —CN,Z is CH; R¹ is —CH₃, R⁴ is —CH₃ and HAL is —Cl.

According to Scheme C, 5-bromo-6-methoxypyridin-3-amine, where U is—NH₂, Z is CH; R¹ is H, R⁴ is —CH₃, is reacted under standard Suzukireaction conditions as previously described, to provide compounds offormula (X), where U is —NH₂, Z is CH; R¹ is H, R³ is aryl orheteroaryl, and R⁴ is —CH₃. Alternately, a compound of formula (X), maybe prepared from commercially available or synthetically accessiblesuitably substituted pyridine amines, such as,5-bromo-6-ethoxypyridin-3-amine, as outlined in the procedures describedabove, where U is —NH₂, Z is CH; R¹ is H, R³ is aryl or heteroaryl, andR⁴ is —C₁₋₃alkyl.

According to Scheme D, a compound of formula (XII), under Sandmeyerconditions known to one skilled in the art, are reacted with anoxidizing agent, such as, but not limited to, tert-butyl nitrite, in thepresence of a halogenating agent, for example copper(II)bromide, in anappropriate solvent, such as ACN and the like, at a suitabletemperature, preferably 60° C., affords a compound of formula (XIII).Lithiation of a compound of formula (XIII) with a suitable metallo-base,such as n-BuLi or the like, in a non-protic solvent, such as THF, Et₂Oor the like, at a low temperature, preferably −78° C., for a period of30-60 minutes, prior to addition of an appropriate aryl orheteroarylcarbonyl compound, followed by additional stirring attemperatures ranging from −78° C. to ambient temperature, provides acompound of Formula (I), where Y is CHOH, Z is CH, R² and R³ aremonocyclic aromatic or heteroaromatic rings, and R⁴ is —CH₃.

A fluoro compound of Formula (I), where Y is —C(R^(a))₂—, and R^(a) is—H or —F; is prepared by the reaction of an alcohol of Formula (I),where Y is CH(OH), employing fluorinating conditions such, but notlimited to, reaction with Deoxo-Fluor®, XtalFluor® and the like, in asolvent such as DCM and the like, at room temperature, for a period of 1to 24 h.

A compound of Formula (I), where Y is —C(R^(a))₂—, and R^(a) is —H isprepared by treating an alcohol of Formula (I), where Y is CH(OH), witha reducing agent, such as but not limited to triethylsilane in thepresence of an acid source, such as trifluoroacetic acid, triflic acidand the like, in a solvent such as DCM and the like, at roomtemperature, for a period up to 24 h.

An amine compound of Formula (I), where Y is —CHNH₂—, —CHNH(CH₃)—, or—CHN (CH₃)₂—, is prepared in two steps by the reaction of an alcohol ofFormula (I), where Y is —CH(OH), with a chlorinating agent, such asthionyl chloride, oxalyl chloride and the like, with or without acatalytic amount of DMF, in a solvent such as DCM, and the like, attemperatures ranging from 0° C. to room temperature to provide thechloro intermediate which is then reacted with the appropriate amine,such as, but not limited to ammonia, methylamine and the like, with orwithout a catalytic amount of sodium iodide, in solvent such as ACN, ata temperature ranging from room temperature to 80° C.

As described in Scheme E, a compound of Formula (I) can be obtained froma compound of formula (IX) thru a reaction such as, but not limited to,Suzuki or Negishi coupling reactions, and substitution reactions withnitrogen heteroaryls. A compound of formula (IX) is reacted, employingstandard Suzuki coupling conditions, known to those skilled in the artand previously described herein, with commercially available aromatic orheteroaromatic boronic acids, boronic esters, trifluoroborates orsynthetically accessible heteroaromatic boronic esters, such as compound(IV), to give a compound of Formula (I). In an alternate method, acompound of formula (IX), where HAL is —Cl, is reacted with dipinacoldiboron, a suitable base such as K₂CO₃, a palladium catalyst such asPd(PPh₃)₄, and the like, in a solvent such as dioxane, to provide thecorresponding boronate ester. Subsequent reaction of the boronate esterwith a suitably halo substituted heteroaryl compound employing Suzukireaction conditions previously described, provides a compound of Formula(I).

A compound of formula (IX) is reacted, employing standard Negishicoupling conditions, known to those skilled in the art. An example ofNegishi reaction conditions are: coupling commercially available halogencontaining aromatic or heteroaromatic intermediates, with a preformedzincate obtained from reacting compounds of formula (IX) with zinc,pretreated with activators such as trimethylsilyl chloride and1,2-dibromoethane, in an appropriate solvent, such as THF, 1,4-dioxane,and the like, at a temperature ranging from room temperature to refluxtemperature, preferably reflux temperature, for a period of 12 to 24 h.Combining the zincate intermediate with commercially available halogencontaining aromatic or heteroaromatic compounds in the presence of apalladium catalyst, such as Pd(PPh₃)₄ and the like, in a suitablesolvent, such as THF, 1,4-dioxane, and the like, at temperatures rangingfrom 50° C. to the reflux temperature of the solvent, for a period of 12to 48 h, affords a compound of Formula (I), where R² is a six memberedheteroaryl ring containing one to two nitrogen members.

A compound of formula (IX) when combined with the appropriateheterocycle (HET) with an acidic proton, such as but not limited to,1H-1,2,4-triazole or imidazole, in an aprotic solvent, for example DMF,acetone, ACN, and the like, with a suitable base, such as Cs₂CO₃, K₂CO₃,and the like, at temperatures ranging from room temperature to 60° C.,for period of 2 to 24 h, provides a compound of Formula (I), where R² isa five membered heteroaryl ring containing two to three nitrogenmembers.

A compound of Formula (I), where Y is —CH₂, and R² is an optionallysubstituted 1,2,3-triazole is obtained using “Click Chemistry” (forexample, copper-catalyzed azide-alkyne cycloaddition) under conditionsknown to one skilled in the art, for example, by treating a compound offormula (IX) with sodium azide in a suitable solvent, such as DMF,acetone, DMSO, and the like, and base such as K₂CO₃, and the like, attemperatures ranging from room temperature to 100° C., affords the azidointermediate which is then combined with a commercially available orsynthetically accessible alkyne, such as but not limited toethynyltrimethylsilane, and the like, in a solvent such as DMSO,1,4-dioxane, THF, ACN, t-butanol, and water or a mixture thereof, in thepresence of a catalyst, for example copper(II)iodide, copper(II)bromide,copper(I)sulfate, and the like, and base, such as DIPEA, and the like,at temperatures ranging from room temperature to 100° C., for a periodof 2 to 12 h, provide a compound of Formula (I), where R² is anoptionally substituted 1,2,3-triazole.

A compound of Formula (I), where R² is substituted with an amide(—CONH₂), is prepared from the corresponding nitriles (—CN) or esters(—CO₂C₁₋₃alkyl) using methods known to those skilled in the art. Forexample, an amide of Formula (I) is obtained by reaction of a nitrilecompound of Formula (I) with a base, such as NaOH or KOH, preferablyNaOH, and a peroxide, such as H₂O₂, in a solvent such as MeOH, and thelike, at a temperatures ranging from 0 to 50° C., for a period of 8 to24 h. Optionally, a carboxylic acid compound of Formula (I) are obtainedwhen nitrile compound of Formula (I) are treated as described above at atemperature of 50° C., for a period of 2 to 4 h. An ester compound ofFormula (I) is converted to an amide of Formula (I) by treating with anappropriate amine, such as ammonia, methylamine or the like, in asolvent, such as MeOH, 1,4-dioxane, and the like, at temperaturesranging from room temperature to the reflux temperature of the solvent.

A compound of Formula (I), where R² is substituted with a primary(—(CH₂)₁₋₂OH) or tertiary (—C(CH₃)₂OH) alcohol is prepared from acorresponding aldehyde or ester compound of Formula (I), using methodsknown to those skilled in the art. Reduction of an aldehyde compound ofFormula (I) with a reducing agent, such as NaBH₄ or NaBH₃CN, and thelike, in a solvent such as MeOH, THF, DMF and the like, at temperaturesranging from 0° C. to room temperature, for a period of 0.2 to 2 h,affords a primary alcohol compound of Formula (I), where R² issubstituted with —CH₂OH. A compound of Formula (I), where R² issubstituted with an ester moiety, is reduced, with a reducing agent,such as NaBH₄, LiBH₄, LAH, DIBAL and the like, with our without KF, in asolvent such as MeOH, THF, Et₂O and the like, at temperatures rangingfrom 0° C. to room temperature, for a period of 2 to 24 h, to afford aprimary alcohol compound of Formula (I), where R² is substituted with—CH₂OH.

A compound of Formula (I), where R² is substituted with —CH₂OH or —CHO,is fluorinated, employing fluorinating conditions such as, but notlimited to, reaction with Deoxo-Fluor®, XtalFluor® and the like, in asolvent such as DCM and the like, room temperature, for a period of 2 to24 h, to provide a fluoroalkyl compound of Formula (I), where R² issubstituted with —CH₂F or —CHF₂.

A compound of Formula (I), where R² is substituted with an ester moiety,is reacted under Grignard conditions known to one skilled in the art,with a Grignard reagent such as, but not limited to, methylmagnesiumbromide, in a solvent such as THF, Et₂O, and the like, at temperaturesranging from 0° C. to room temperature, for a period of 0.3 to 2 h, toprovide a compound of Formula (I), where R² is substituted with atertiary alcohol (—C(CH₃)₂OH).

A compound of Formula (I), where R² is substituted with —CN, is reducedwith a reducing agent, such as DIBAL and the like, in a solvent such asEt₂O, THF, and the like, at low temperatures, preferably −78° C., for aperiod of 1 to 4 h, to provide a primary amine compound of Formula (I),where R² is substituted with primary amine (—CH₂NH₂).

A compound of Formula (I), where R² is substituted with —CN, is reactedwith acetyl chloride, in an alcoholic solvent such as MeOH, EtOH, andthe like, a at low temperature, preferably 0° C., for a period of 30min. to 2 h, provides a compound of Formula (I), where R² is substitutedwith CO₂C₁₋₃alkyl.

A compound of Formula (I), where R² is substituted with —CH₂CN, isreacted under alkylating conditions, known to one skilled in the art, toprovide a compound of Formula (I), where R² is substituted with—C(CH₃)₂CN. For example, reaction with an alkylating agent such as MeI,a base such as NaOH, a solvent such as DMSO, water, or a mixturethereof, at low temperatures such as 0° C., for a period of 30 min. to 2h.

A compound of Formula (I), where R² is substituted with an ester moiety,is reacted under standard hydrolysis conditions known to one skilled inthe art, with a base such as, but not limited to, KOH, LiOH, NaOH andthe like, in a solvent such as THF, 1,4-dioxane, MeOH, H₂O or a mixturethereof, at temperatures ranging from room temperature to the refluxtemperature of the solvent, for a period of 1 to 4 h, to provide acompound of Formula (I), where R² is substituted with carboxylic acid(—CO₂H).

A compound of Formula (I), where R² is substituted with an amide(—CONH₂) is prepared in two steps from a compound of Formula (I), whereR² is substituted with carboxylic acid (—CO₂H). Halogenation to the acidchloride employing known methods, followed by reaction with an ammoniasource such as ammonia in dioxane, provides a compound of Formula (I),where R² is substituted with an amide (—CONH₂).

A compound of Formula (I), where R² is an optionally substitutedpyrimidine or pyrazine substituted with —Cl or —Br is reacted with alkylor heteroalkyl oxygen or nitrogen nucleophiles, such asN1,N1-dimethylethane-1,2-diamine, 2-aminoethanol, morpholine, and thelike, in a solvent such as ACN, THF, EtOH, DMF, toluene, and the like, abase such as DIPEA, TEA, NaH, K₂CO₃, and the like, at temperatureranging from 50 to 180° C., employing conventional or microwave heatingconditions, for a period of 1 to 4 h, to provide a compound of Formula(I), where R² is an optionally substituted pyrimidine or pyrazine.

A compound of Formula (I), where R² is substituted with —NO₂, is reducedwith a reducing agent, such as, but not limited to zinc or iron, in asolvent such as acetic acid, water, or a mixture thereof, attemperatures ranging from room temperature to 50° C., for a period of 1to 4 h, to provide a primary amine compound of Formula (I), where R² issubstituted with primary amine (—NH₂).

A compound of Formula (I), where R² is substituted with primary amine(—NH₂) is reacted with tert-butyl nitrite, in a solvent such as DMF,water, or a mixture thereof, at temperatures ranging from 0° C. to 60°C., for a period of 8 to 16 h, affords a compound of Formula (I), whereR² is substituted with —OH.

A compound of Formula (I), where R² is substituted with (—NHR^(b)) or(—N(R^(b))₂) is prepared from the corresponding amine compounds ofFormula (I), employing methods known to one skilled in the art, such asbut not limited to a reductive amination reaction. For example, acompound of Formula (I) where R² is substituted with (—NH₂), is reactedwith an appropriate carbonyl intermediate, such as but not limited to,formaldehyde and the like, in a solvent such as THF, DCM, MeOH and thelike, with a reducing agent, such as NaBH(OAc)₃, NaBH₃CN and the like,at temperatures ranging from 0 to 50° C., for a period of 1 to 4 h, toprovide an alkyl amine compound of Formula (I), where R^(b) is —CH₃.

A compound of Formula (I), where R² is substituted with (—NHCOCH₃) isprepared from the corresponding amine compound of Formula (I), employingmethods known to one skilled in the art, such as but not limited to,treatment with an acyl chloride or anhydride. For example, a compound ofFormula (I) where R² is substituted with (—NH₂), is treated with anappropriately activated acylating agent, such as but not limited to,acetyl chloride, acetic anhydride and the like, in a solvent such as,DCM, DMF and the like, with a base, such as TEA, DIPEA, and the like, attemperatures ranging from 0° C. to room temperature, for a period of upto 24 h, provides an acyl substituted amine compound of Formula (I),where R² is (—NHCOCH₃).

A compound of Formula (I), where R² is substituted with (—NHCONH₂) isprepared from a corresponding amine compound of Formula (I), employingmethods known to one skilled in the art, such as but not limited to,treatment with potassium cyanate and the like, in a solvent such as,acetic acid and water or a mixture thereof, at temperatures ranging fromroom temperature to 60° C., for 0.2 to 4 h, to provide a ureasubstituted compound of Formula (I), where R² is (—NHCONH₂). Optionally,a compound of Formula (I), where R² is substituted with(—NHCONH-oxetane) is prepared from the corresponding carboxylic acidcompounds of Formula (I), using the Curtuis rearrangement employingmethods known to one skilled in the art. For example, a compound ofFormula (I) where R² is substituted with (—CO₂H), are treated with, butnot limited to, diphenylphosphoryl azide and the like, in the presenceof a base, such as TEA, DIPEA, and the like, in an appropriate solventsuch as, toluene, 1,-4-dioxane, and the like, at the reflux temperatureof the solvent, for a period of up to 1 h. The intermediate acyl azideis then reacted with an appropriate amine, in the presence of a base,such as TEA, DIPEA, and the like, to afford a compound of Formula (I)where R² is substituted with (—NHCONH-oxetane).

A compound of Formula (I), where R² is substituted with —NO₂, is reactedwith a commercially available or synthetically accessiblemetallo-alkoxide, for example, sodium methoxide, sodium ethoxide and thelike, in a solvent such as, but not limited to, MeOH, EtOH, 1,4-dioxaneand the like, at temperatures ranging from room temperature to thereflux temperature of the solvent, for a period of 24 h, to provide acompound of Formula (I) where R² is substituted with (—OC₁₋₃alkyl).

A compound of Formula (I), wherein R² is 1,2,3-triazole optionallysubstituted with —H, is synthesized from the corresponding4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl) compounds of Formula (I), byreacting with a desilylating agent, such as but not limited to,tetrabutylammonium fluoride, in a solvent such as THF, DMF, and thelike, at temperatures ranging from room temperature to 50° C., for aperiod of 8 to 24 h.

A compound of Formula (I), where R² is substituted with —CHO, isprepared from the corresponding alcohols or esters, previously describedusing methods known to those skilled in the art. For example, treatingan alcohol of Formula (I) with an oxidizing agent, such as but notlimited to Dess-Martin® reagent, in an appropriate solvent, such as DCMor THF and the like, at room temperature for 3 to 8 h give the desiredaldehyde. The desired aldehyde of Formula (I) is also obtained bytreating the corresponding ester of Formula (I) with a reducing agent,such as DIBAL, in an appropriate solvent, such as THF, Et₂O and thelike, at low temperature, preferably −78° C., for 1 to 4 h.

Removal of the tert-butylcarbamate (BOC) or paramethoxybenzyl (PMB) in acompound of Formula (I) where R² is optionally substituted with(—NH—BOC), (-HET-N—BOC), (—NH-PMB) is accomplished by using methodsknown to one skilled in the art, such as, HCl, TFA, or p-toluenesulfonicacid, in a solvent such as CH₃OH, dioxane, or CH₂CI₂. In a preferredembodiment, a compound of formula is treated with TFA in DCM or HCl toafford a compound of Formula (I) where R² is optionally substituted with(—NH₂) or (-HET-NH₂).

According to Scheme F, a compound of formula (VI) where U is —CH₃; R¹ isH, R⁴ is —C₁₋₃alkyl or —C₁₋₃haloalkyl, is halogenated according tomethods previously described to provide the corresponding alkylbromidecompound. Subsequent reaction with HET, where HET is an optionallysubstituted five membered heteroaryl ring selected from, but not limitedto, 1H-1,2,4-triazole or imidazole, according to methods previouslydescribed, provides a compound of formula (XII) where HET is anoptionally substituted five membered heteroaryl ring.

According to Scheme F, a compound of formula (XII) where HET is anoptionally substituted five membered heteroaryl ring is prepared from acompound of formula (VI) where U is —CH₂Cl, R¹ is H, R⁴ is —C₁₋₃alkyl or—C₁₋₃haloalkyl, employing methods previously described. For example,reaction of (5-bromo-6-ethoxypyridin-3-yl)methanol with an optionallysubstituted five membered heteroaryl ring, a base such as K₂CO₃. Cs₂CO₃,and the like, with or without NaI, in a solvent such as DCM, CHCl₃, ACN,and the like, at temperatures ranging from rt to the reflux temperatureof the solvent, provides a compound of formula (XII).

A compound of formula (XII), where HET is five membered heteroaryl ringoptionally substituted with a —CO₂C₁₋₃alkyl or C(═O)H moiety, isreduced, employing methods known to one skilled in the art or previouslydescribed, to provide a compound of formula (XII), where the HET issubstituted with —CH₂OH. For example, methyl1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylateis reacted with a reducing agent such as LiBH₄, NaBH₄, and the like, ina solvent such as THF, MeOH, and the like, at temperatures ranging from0° C. to rt, for a period of 1 to 5 h, to provide a compound of formula(XII) where HET is substituted with —CH₂OH.

A compound of formula (XII), where HET is five membered heteroaryl ringoptionally substituted with a —NO₂ moiety, is reduced, employing methodsknown to one skilled in the art or previously described, to provide acompound of formula (XII), where the HET is substituted with —NH₂.

A compound of formula (XII) is reacted, employing standard Suzukicoupling conditions, known to those skilled in the art and previouslydescribed herein, with commercially available aromatic or heteroaromaticboronic acids or esters, or synthetically accessible heteroaromaticboronic esters, such as compound (IV), to give a compound of Formula(I).

Optionally, a compound of Formula (I), where R³ is substituted withpyrazole is prepared from the corresponding compounds of formula (XII),employing methods known to one skilled in the art, such as but notlimited to, Buchwald coupling conditions. For example, a compound offormula (XII) is reacted with the appropriate heterocycle (HET) with anacidic proton, such as but not limited to, pyrazole, in a solvent, suchas toluene, 1,4-dioxane, and the like, with a suitable base, such assodium tert-butoxide, sodium methoxide, a palladium catalyst such as butnot limited to, Pd₂(dba)₃, Pd(OAc)₂ and the like, and a phosphineligand, such as (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,tri(tert-butyl)phosphine and the like, at temperatures ranging from roomtemperature to the reflux temperature of the solvent, for period of 4 to48 h, to provide a compound of Formula (I), where insert R³ is anoptionally substituted pyrazole.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, compoundsof Formula (I) may be treated with TFA, HCl, maleic acid, or citric acidin a solvent such as Et₂O, DCM, THF, or MeOH to provide thecorresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastereo-, or regiospecific synthesis, or by resolution.Where compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures of mixturesas diastereomers or regioisomers. Where racemic and non-racemic mixturesof enantiomers are obtained, single enantiomers may be isolated usingconventional separation methods known to one skilled in the art, such aschiral chromatography, recrystallization, diastereomeric salt formation,derivatization into diastereomeric adducts, biotransformation, orenzymatic transformation. Where regioisomeric or diastereomeric mixturesare obtained, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

Examples Chemistry:

In obtaining the compounds described in the examples below, and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under nitrogen atmosphere. Where solutions were“dried”, they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions were carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

LC/MS were obtained on a Waters 2695 Separations Unit, 2487 DualAbsorbance Detector, Micromass ZQ fitted with ESI Probe, or a WatersAcquity™ Ultra performance LC (UPLC) with PDA eλ and SQ detectors.

Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400MHz or Bruker 400 MHz NMR. Samples were analyzed in either deuteratedchloroform (CDCl₃), methanol-d₄ (CD₃OD), or dimethyl sulfoxide-d₆(DMSO-d₆). For CDCl₃ samples, tetramethylsilane (TMS) was used as aninternal standard with the TMS resonance set to a chemical shift of 0.00ppm for ¹H NMR spectra. For CD₃OD the residual central resonance peak at3.31 for ¹H was used for chemical shift assignment and for DMSO-d₆ theresidual central resonance peak at 2.50 ppm for ¹H was used for chemicalshift assignment. The format of the ¹H NMR data below is: chemical shiftin ppm downfield the tetramethylsilane reference (multiplicity, couplingconstant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ChemAxon.

Intermediate 1.5-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine

Step 1. 3-Bromo-5-methylpyrazin-2-amine. To a cooled, 0° C., solution of5-methylpyrazin-2-amine (5.00 g, 0.05 mol) in DCM (230 mL) was added1-bromopyrrolidine-2,5-dione (8.97 g, 0.05 mol) all at once. Thereaction mixture was allowed to warm to room temperature and stirred for12 h. The reaction was quenched with 1 N sodium thiosulfate (50 mL), thelayers were separated and the organic phase was extracted with water(2×50 mL). The combined organic layers were dried (Na₂SO₄), and thesolvent was removed under reduced pressure. Purification (FCC, SiO₂,0-50%, EtOAc/hexanes) afforded the title compound as a yellow solid(8.61 g, 65%). [M+H]=188.9/190.11

Step 2. 3-Bromo-2-ethoxy-5-methylpyrazine. To a solution of3-bromo-5-methylpyrazin-2-amine (4.00 g, 21.27 mmol) in EtOH (42 mL), at0° C., was added tert-butyl nitrite (7.65 mL, 63.82 mmol) followed by 4N HCl in 1,4-dioxane (1.91 mL, 7.66 mmol). The reaction mixture wasallowed to warm to room temperature and stirred for 8 h. The mixture wasconcentrated under reduced pressure. The residue was diluted with aq.NaHCO₃ and extracted into DCM. The combined organic layers were dried,and the solvent was removed under reduced pressure. Purification (FCC,SiO₂, 0-20%, EtOAc/hexanes) afforded the title compound as a white solid(2.5 g, 54%). [M+H]=217.06/219.05.

Step 3. 3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine. Asolution of 3-bromo-2-ethoxy-5-methylpyrazine (1.80 g, 8.29 mmol),3-(difluoromethoxy)phenyl)boronic acid (2.03 g, 10.78 mmol), Pd(PPh₃)₄(958.25 mg, 0.83 mmol), Na₂CO₃ (21.63 mL, 1.15 mol/L, 24.88 mmol), inEtOH (22 mL) and toluene (118 mL), under nitrogen, was heated at 88° C.for 1 h. The reaction mixture was extracted with EtOAc. The combinedorganic layers were dried (Na₂SO₄), and the solvent was removed underreduced pressure. Purification (FCC, SiO₂, 0-50%, EtOAc/hexanes)afforded the title compound as a colorless oil (2.09 g, 90%).[M+H]=281.19.

Step 4. 5-(Bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine.To a solution of 3-(3-(difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine(2.00 g, 0.01 mol), 1-bromopyrrolidine-2,5-dione (1.27 g, 0.01 mol) incarbon tetrachloride (24 mL), was added benzoylperoxide (0.26 g, 1.07mmol). The mixture was heated at 88° C. for 8 h. The reaction mixturewas diluted with water and extracted with DCM. The combined organiclayers were dried (Na₂SO₄) and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 0-5%, EtOAc/hexanes) afforded thetitle compound contaminated with ˜10% starting material (1.5 g, 59%).[M+H]=459.13/361.13.

Intermediates 2-3 were prepared in a manner analogous to Intermediate 1,Steps 3-4, with the appropriated starting material substitutions.

Intermediate 2. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine

M+H]=312.05/314.04

Intermediate 3. 5-(Bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine

[M+H]=313.17/315.19

Intermediate 4. 3-Bromo-2-(difluoromethoxy)-5-methylpyridine

3-Bromo-2-(difluoromethoxy)-5-methylpyridine. To a solution of3-bromo-5-methylpyridin-2-ol (25.0 g, 0.13 mol) in ACN (100 mL) wasadded 2,2-difluoro-2-(fluorosulfonyl)acetic acid (23.7 g, 0.13 mol) andNa₂CO₃ (28.2 g, 0.270 mol). The reaction mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture, and thereaction mixture was extracted with DCM. The combined organic layerswere dried (Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-10%, EtOAc/hexanes) afforded the titlecompound as an off-white solid (22 g, 70%). [M+H]=238.09/240.09.

Intermediate 5.5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine

Step 1. 3-Bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine. To asolution of 3-bromo-2-(difluoromethoxy)-5-methylpyridine (0.50 g, 2.1mmol) in carbon tetrachloride (13 mL), was added1-bromopyrrolidine-2,5-dione (0.521 g, 2.93 mmol), andazobisisobutyronitrile (44 mg, 0.26 mmol). The reaction mixture wasstirred at 80° C. for 8 h. The reaction mixture was diluted with waterand extracted with DCM. The combined organic layers were dried (Na₂SO₄),and the solvent was removed under reduced pressure. Purification (FCC,SiO₂, 10-90%, EtOAc/hexanes) afforded the title compound (400 mg, 60%).[M+H]=317.88.

Step 2.5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine.To a solution of 3-bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine(Intermediate 4, 0.50 g, 1.57 mmol), in acetone (12 mL), was added1H-1,2,4-triazole (202 mg, 2.9 mmol), and K₂CO₃ (650 mg, 4.7 mmol). Thereaction mixture stirred at room temperature for 2 h, then filtered andconcentrated under reduced pressure. Purification (FCC, SiO₂, 30-70%,EtOAc/hexanes) afforded the title compound (431 mg, 90%).[M+H]=304.91/306.91.

Intermediate 6. 3-Bromo-2-ethoxy-5-methylpyridine

To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol)in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) inthree portions. The mixture was stirred under nitrogen at 100° C. for 2days. The reaction was cooled to room temperature, diluted with waterand extracted with DCM. The combined organic layers were dried (Na₂SO₄),and the solvent was removed under reduced pressure. Purification (FCC,SiO₂, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). ¹HNMR (400 MHz, DMSO-d₆) δ 7.94 (dd, J=0.8, 2.3 Hz, 1H), 7.89-7.82 (m,1H), 4.31 (q, J=7.0 Hz, 2H), 2.18 (t, J=0.8 Hz, 3H), 1.30 (t, J=7.0 Hz,3H).

Intermediate 7. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine

Step 1. 5-(3-Chlorophenyl)-6-methoxypyridin-3-amine. A 10 mL microwavevial was charged with 5-bromo-6-methoxypyridin-3-amine (2.00 g, 10 mmol)(3-chlorophenyl)boronic acid (1.87 g, 12 mmol), Pd(dppf)Cl₂.DCM (365 mg,0.45 mmol), ACN (6 mL) and sat. aq. NaHCO₃ (3 mL). The vial was sealed,purged with nitrogen and heated at 110° C. for 15 min. The layers wereseparated and the aq. phase extracted with EtOAc. The combined organiclayers were dried (Na₂SO₄), and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 0-50%, EtOAc/hexanes) afforded thetitle compound (1.95 g, 84%) which was taken on directly to the nextstep.

Step 2. 5-Bromo-3-(3-chlorophenyl)-2-methoxypyridine. A solution of5-(3-chlorophenyl)-6-methoxypyridin-3-amine (1.95 g, 8.39 mmol), copper(II) bromide (3.72 g, 16.7 mmol), tert-butyl nitrite (1.7 g, 16.7 mmol)in ACN (50 mL), under nitrogen, was heated at 60° C. for 12 h. Thereaction mixture was concentrated under reduced pressure. Purification(FCC, SiO₂, 0-10%, EtOAc/hexanes) afforded the title compound as anorange solid (1.53 g, 61%). [M+H]=298.20/300.21.

Intermediate 8.3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine

Step 1. 6-Amino-5-bromo-2-methylnicotinonitrile. A solution of6-amino-2-methylnicotinonitrile (5 g, 37.6 mmol), NBS (7.36 g, 41.3mmol) and DCM (100 mL) was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure. Purification(FCC, SiO₂, 1:1 EtOAc/DCM) afforded the title compound as tan solid (4.5g, 56%). [M+H]=211.95/213.96.

Step 2. 5-Bromo-6-methoxy-2-methylnicotinonitrile. A solution of6-amino-5-bromo-2-methylnicotinonitrile (4.5 g, 21.2 mmol), HCl (2 mL 4N HCl in 1,4-dioxane), tert-butyl nitrite (6.56 g, 63.7 mmol) andmethanol (50 mL) was heated at 60° C. for 12 h. The solvent was removedunder reduced pressure. Purification (FCC, SiO₂, 0-25%, EtOAc/hexanes)afforded the title compound (2.5 g, 51%). [M+H]=226.96/228.96.

Step 3. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinonitrile. A 20 mLmicrowave vial was charged with5-bromo-6-methoxy-2-methylnicotinonitrile (1.2 g, 5.28 mmol),(3-chlorophenyl)boronic acid (990 mg, 6.3 mmol), Pd(dppf)Cl₂. DCM (191mg, 0.26 mmol), ACN (10 mL) and sat. aq. NaHCO₃ (3 mL). The vial wassealed, purged with nitrogen and heated at 100° C. under microwaveirradiation for 10 min. The layers were separated and the aq. phaseextracted with EtOAc. The combined organic layers were dried (Na₂SO₄),and the solvent was removed under reduced pressure. Purification (FCC,SiO₂, 0-50%, EtOAc/hexanes) afforded the title compound as an off whitesolid (995 mg, 74%). [M+H]=259.06.

Step 4. 5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. To acooled solution, −78° C., of5-(3-chlorophenyl)-6-methoxy-2-methylnicotinonitrile (500 mg, 1.9 mmol)in DCM (15 mL), under nitrogen, was added DIBAL (1 M in hexanes, 4.8 mL,4.8 mmol) drop-wise, over 3 minutes. The reaction mixture was stirred at−78° C. for 1 h. The reaction was carefully quenched by addition ofsaturated sodium fluoride (1 mL). After stirring for 30 minutes thesuspension was filtered and the filtrate concentrated under reducedpressure. Purification (FCC, SiO₂, 0-50%, EtOAc/hexanes) afforded thetitle compound (358 mg, 72%). [M+H]=262.05.

Step 5. (5-(3-Chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol. Toa solution of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinaldehyde (350mg, 1.34 mmol) in methanol (3 mL) was added NaBH₄ (52 mg, 1.3 mmol). Thesolution was stirred at room temperature for 20 minutes thenconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-50%,EtOAc/hexanes) afforded the title compound (322 mg, 91%). [M+H]=264.06.

Step 6. 3-(Chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine.Into a scintillation vial containing(5-(3-chlorophenyl)-6-methoxy-2-methylpyridin-3-yl)methanol (340 mg,1.29 mmol) in DCM (5 mL), was added diisopropylethylamine (199 mg, 1.54mmol), and methanesulfonyl chloride (147 mg, 1.29 mmol). The solutionwas stirred at room temperature for 1 h. The reaction mixture wasextracted with water (3×). The combined organic layers were dried(Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-30%, EtOAc/hexanes) afforded the titlecompound (87 mg, 24%). [M+H]=282.03

Intermediate 9.2-Difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

Step 1. 4-Bromo-2-(difluoromethoxy)pyridine. To a stirring solution of2-chloro-2,2-difluoroacetate (6.00 g, 39.4 mmol) in ACN (200 mL) wasadded 4-bromopyridin-2(1H)-one (4.90 g, 28.1 mmol). The mixture wasrefluxed for 8 h. The resulting mixture was filtered and the filtratewas extracted with hexanes (6×20 mL). The combined organic layers weredried (Na₂SO₄), and concentrated at room temperature to give the titlecompound as a liquid (2.60 g, 42% yield). ¹H NMR (400 MHz, DMSO-d₆) δ8.19-8.20 (s, 1H), 7.48 (s, 1H), 7.52 (s, 1H), 7.54-7.88 (m, 1H).

Step 2.2-Difluoromethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine.To a solution of 4-bromo-2-(difluoromethoxy)pyridine (7.20 g, 32.1mmol), in 1,4-dioxane (230 mL), was added bis(pinacolato)diboron (8.80g, 34.6 mmol), and potassium acetate (7.10 g, 71.9 mmol). The flask wasfitted with a reflux condenser and vacuum/nitrogen inlet, and it wasdegassed/backfilled with nitrogen (3×). The catalyst, Pd(dppf)Cl₂ (2.35g, 3.2 mmol) was added, and the reaction mixture was refluxed for 8 h.The resulting mixture was filtered, and concentrated under reducedpressure. Purification (FCC, SiO₂, 1:1 petroleum ether/hexanes) affordedthe title compound (6.10 g, 70%) as a liquid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.31-8.32 (d, J=4.8 Hz, 1H), 7.52-7.89 (m, 1H), 7.42-7.44 (d, J=4.8Hz, 1H), 7.156 (s, 1H), 1.32 (s, 12H).

Intermediate 10.5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine

Step 1. 3-(2-(Difluoromethoxy)-5-methylpyridin-3-yl)phenol. A 20 mLmicrowave vial was charged with3-bromo-2-(difluoromethoxy)-5-methylpyridine (Intermediate 4, 1.90 g,7.98 mmol), 3-hydroxyphenylboronic acid (1.32 g, 9.58 mmol), Pd(dppf)Cl₂(330 mg, 0.40 mmol), Na₂CO₃ (2.12 g, 19.96 mmol), water (4.0 mL), andACN (12 mL). The vial was sealed, purged with nitrogen, and heated undermicrowave irradiation at 100° C. for 15 min. The reaction mixture wasdiluted with water and extracted with DCM (3×). The combined organicphase was dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification (FCC, SiO₂, 0-40% EtOAc/hexanes) afforded thetitle compound (1.81 g, 91%) as a colorless waxy solid. [M+H]=252.12.

Step 2.2-(Difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine. To asolution of 3-(2-(difluoromethoxy)-5-methylpyridin-3-yl)phenol (502.5mg, 2.0 mmol), in DMF, was added oxetan-3-yl 4-methylbenzenesulfonate(685 mg, 3.0 mmol), and K₂CO₃ (553 mg, 4.00 mmol). The reaction mixturewas stirred at 60° C. for 8 h. LC-MS suggested about 50% conversion. Thetemperature was raised to 90° C. and the reaction mixture was stirred anadditional 4 h. Sat. aq. NaCl was added, and the mixture was extractedwith DCM (3×). The combined organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification (FCC, SiO₂, 10-30%EtOAc/hexanes) afforded the title compound (310 mg, 50%) as a colorlesssolid. [M+H]=308.11

Step 3.5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine.To a solution of2-(difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine (310mg, 1.0 mmol) in carbon tetrachloride (10 mL), was added1-bromopyrrolidine-2,5-dione (180 mg, 1.0 mmol), and benzoylperoxide (37mg, 0.15 mmol). The reaction mixture was stirred at 80° C. for 8 h. Thereaction mixture was diluted with water and extracted with DCM. Thecombined organic layers were dried (Na₂SO₄), and the solvent was removedunder reduced pressure. Purification (FCC, SiO₂, 10-30%, EtOAc/hexanes)afforded the title compound (140 mg, 36%). [M+H]=387.21

Intermediate 11.5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-isopropoxyphenyl)pyridine

The title compound was prepared in a manner analogous to Intermediate10, using 2-bromopropane for step 2, followed by bromination accordingto step 3. [M+H]=373.24.

Intermediate 12.5-(Bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine

The title compound was prepared in a manner analogous to Intermediate10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1,followed by bromination according to Step 3. [M+H]=348.17/350.15

Intermediate 13.5-((1H-1,2,4-Triazol-1-yl)methyl)-3-bromo-2-methoxypyridine

The title compound was prepared in a manner analogous to Intermediate 5,with the appropriate starting material substitutions.[M+H]=269.21/271.23

Intermediate 14. Ethyl 5-bromo-6-ethoxynicotinate

Step 1. 5-Bromo-6-chloronicotinoyl chloride. To a solution of5-bromo-6-chloronicotinic acid (10.00 g, 42.29 mmol) in DCM (211.46 mL)was added oxalyl dichloride (42.29 mL, 84.58 mmol) and a few drops ofDMF. The reaction mixture was stirred at room temperature for 3 h. Thesolvent was removed under reduced pressure to afford the crude titlecompound (9.0 g, 83%). The crude material was used without furtherpurification. [M+H]=253.2/255.2/257.2.

Step 2. Ethyl 5-bromo-6-ethoxynicotinate. To a slurry of5-bromo-6-chloronicotinoyl chloride (5.00 g, 19.62 mmol) in EtOH (100mL) was added sodium ethoxide (22.0 mL, 21.00% w/w, 58.85 mmol). Thereaction mixture was stirred in room temperature for 75 minutes. Theproduct crystallized out after the addition of 2 volumes of water in anice bath. The solid was filtered, washed with hexanes and water toobtain the title compound (4.5 g, 84%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.66(br s, 1H), 8.34 (br s, 1H), 4.48-4.37 (m, 2H), 4.37-4.16 (m, 2H), 1.32(td, J=6.9, 18.7 Hz, 6H); [M+H]=274.3/276.3.

Intermediate 15. Methyl 5-bromo-6-methoxynicotinate

To a slurry of methyl 5-bromo-6-chloronicotinate (10.00 g, 39.92 mmol)in MeOH (80.00 mL) was added sodium methoxide (2.59 g, 47.91 mmol). Thereaction mixture was stirred in rt for 2 h. The product crystallizedout. The slurry was cooled to 0° C. and water (80 mL) was added andstirred for 30 min., then filtered. The solid cake was washed with waterand dried to afford the title compound (9.05 g, 92%). [M+H]=246.2.

Intermediate 16. (5-Bromo-6-ethoxypyridin-3-yl)methanol

A solution of ethyl 5-bromo-6-ethoxynicotinate (Intermediate 14, 1.06 g,3.85 mmol) in 2-methoxy-2-methylpropane (10.50 mL) was cooled to 0° C.and DIBAL (9 mL, 9.00 mmol) was slowly added while keeping thetemperature under 25° C. After the addition was complete, the mixturewas stirred at room temperature for 45 minutes. The reaction was cooledto 0° C., then quenched with aq NaOH (5.78 mL, 11.56 mmol) and stirredat room temperature for 1 h. The mixture was diluted with MTBE andwater, then extracted into MTBE. The combined organic extracts weredried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford the title compound (0.87 g, 97%) as a white solid. The crudematerial was used without further purification. [M+H]=232.3/234.3.

Intermediate 17. 3-Bromo-5-(chloromethyl)-2-ethoxypyridine

A solution of (5-bromo-6-ethoxypyridin-3-yl)methanol (13.44 g, 57.91mmol) in DCM (250 mL) was cooled to 0° C. and thionyl chloride (6.74 mL,92.63 mmol) was slowly added. After the addition was complete, themixture was stirred at room temperature for 30 minutes. The reactionmixture was diluted with DCM (250 mL), and the pH was adjusted to basicpH with a sat. aq. solution of NaHCO₃. The crude product was extractedinto DCM (3×250 mL) and the combined organic extracts were washed withwater (100 mL). The organics were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford the title compound (13.6g, 94%). The crude material was used without further purification.[M+H]=250.2/252.2.

Intermediate 18. Methyl1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

A solution of 3-bromo-5-(chloromethyl)-2-ethoxypyridine (13.60 g, 54.29mmol), CHCl₃ (250 mL), 18-Crown-6 (12.20 g, 46.14 mmol), K₂CO₃ (15.01 g,108.57 mmol) and methyl 1H-1,2,4-triazole-3-carboxylate (10.70 g, 84.18mmol) was stirred at 35° C. for 17 h. Celite® was added to the reactionand the mixture concentrated in vacuo to give the crude material fusedto Celite®. Purification (FCC, SiO₂, 10-100% EtOAc/hexanes) afforded thetitle compound (11.76 g, 64%). [M+H]=341.3/343.3.

Intermediate 19.(1-((5-Bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol

(1-((5-Bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol.A solution of methyl1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(11.76 g, 34.47 mmol) in THF (100 mL) was cooled to 0° C., LiBH₄ (787.00mg, 36.13 mmol) added and the mixture was warmed to 25° C. over 3 h.Water (10 mL), 1N NaOH (10 mL) and Celite® were added to the reactionand the mixture concentrated in vacuo to give the crude material fusedto Celite®. Purification (FCC, SiO₂, 0-15% MeOH/DCM) afforded the titlecompound (9.36 g, 87%) as a white solid. [M+H]=313.3/315.3.

Intermediate 20. (5-Bromo-6-propoxypyridin-3-yl)methanol

Step 1. 5-Bromo-6-propoxynicotinic acid. A mixture of5-bromo-6-chloronicotinic acid (2.00 g, 8.46 mmol), propan-1-ol (10 mL,133.69 mmol) and Cs₂CO₃ (5.51 g, 16.92 mmol) were irradiated in amicrowave at 120° C. for 1 h. The mixture was additionally irradiated afurther 8 h at 120° C. The mixture was diluted with DCM (100 mL) andwater (100 mL). The aqueous layer was made acidic with 1 N aq. HCl, andextracted into DCM (3×100 mL). The combined organic extracts were washedwith sat. aq. NaCl (100 mL), dried (Na₂SO₄), filtered and concentratedunder reduced pressure to afford the title compound (2.04 g, 93%) as acream solid. The crude material was used without further purification.¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (s, 1H), 8.59-8.76 (m, 1H), 8.35 (d,J=1.96 Hz, 1H), 4.28-4.45 (m, 2H), 1.61-1.86 (m, 2H), 0.99 (t, J=7.43Hz, 3H); [M+H]=260.3/262.3.

Step 2. (5-Bromo-6-propoxypyridin-3-yl)methanol. A mixture of5-bromo-6-propoxynicotinic acid (1.61 g, 6.19 mmol), THF (15.06 mL) andTEA (1.73 mL, 12.38 mmol) was cooled to 0° C., methyl chloroformate(0.72 mL, 9.29 mmol) added and the mixture stirred at 0° C. for 2 h. Themixture was filtered, (the solid) rinsed with more THF (20 mL), cooledto 0° C., NaBH₄ (0.47 g, 12.38 mmol) added and the mixture stirred at 0°C. for 90 min. LiBH₄ (0.18 g, 8.05 mmol) was added and the mixturestirred at room temperature for 17 h. The reaction mixture was dilutedwith DCM (100 mL) and water (100 mL), the layers separated and theaqueous layer extracted into DCM (3×80 mL). The extracts were dried(Na₂SO₄), filtered, Celite® added and the solvent removed to give thecrude alcohol fused to Celite®. Purification (FCC, SiO₂, 5-40%EtOAc/hexanes) afforded the title compound (966 mg, 63%).[M+H]=246.3/248.3.

Intermediate 21. (5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methanol

Nitrogen gas was bubbled through a solution of(5-bromo-6-propoxypyridin-3-yl)methanol (Intermeidate 20,483 mg, 1.96mmol), (3,4-difluorophenyl)boronic acid (464.8 mg, 2.94 mmol), K₂CO₃(813.7 mg, 5.89 mmol) in water (2.9 mL), Pd(dppf)Cl₂ (215.4 mg, 0.29mmol) added and the mixture irradiated with stirring in a microwave at120° C. for 20 minutes. Celite® was added to the reaction and themixture concentrated in vacuo to give the crude material fused toCelite®. Purification (FCC, SiO₂, 5-100% EtOAc/hexanes) afforded thetitle compound (547 mg, 100%). [M+H]=280.4.

Intermediate 22.5-(Chloromethyl)-3-(3,4-difluorophenyl)-2-propoxypyridine

The title compound was prepared in a manner analogous to Intermediate17, substituting (5-(3,4-difluorophenyl)-6-propoxypyridin-3-yl)methanol(Intermediate 21) for (5-bromo-6-ethoxypyridin-3-yl)methanol.[M+H]=298.4.

Intermediate 23. (5-Bromo-6-methoxypyridin-3-yl)methanol

To a solution of methyl 5-bromo-6-methoxynicotinate (8.00 g, 32.51 mmol)in THF (162.56 mL) was added LiBH₄ (1.06 g, 48.77 mmol). MeOH (40.64 mL)was slowly added to the reaction, with vigorous stirring. The reactionwas allowed to stir at room temperature for 2 h. 2N NaOH was added tothe reaction mixture the mixture was stirred at room temp for 1 h. Thecrude mixture was added to EtoAc and H₂O, the organic layer wasseparated, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification (FCC, SiO₂) afforded the title compound (6.00 g,84%). [M+H]=218.2.

Intermediate 24. (5-(4-Fluorophenyl)-6-methoxypyridin-3-yl)methanol

A solution of (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23,2.45 g, 11.24 mmol), (4-fluorophenyl)boronic acid (1.97 g, 14.05 mmol),Na₂CO₃ (29.31 mL, 1.15 mol/L, 33.71 mmol) and Pd(dppf)Cl₂ (822.15 mg,1.12 mmol) in ACN (74.91 mL) was heated under microwave conditions at120° C. for 20 min. The aq. layer was removed and the organic layer wasdried (Na₂SO₄). The Na₂SO₄ was washed with EtOAc (3×15 mL). Purification(FCC, SiO₂, 10% MeOH/90% EtOAc) afforded the title compound (2.0 g,76%). [M+H]=234.50.

Intermediate 25. 3-Bromo-5-(chloromethyl)-2-methoxypyridine

The title compound was prepared in a manner analogous to Intermediate 17using Intermediate 23. [M+H]=235.9/237.9.

Intermediate 26.3-(3-Chloro-4-fluorophenyl)-5-(chloromethyl)-2-methoxypyridine

The title compound was prepared in a manner analogous to Intermediate17. [M+H]=286.25.

Intermediate 27. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine

To a mixture of 6-methoxy nicotinaldehyde (24 g, 0.175 mol) and NaOAc(28.7 g, 0.35 mol) in HOAc (180 mL) was added Br₂ (42 g, 0.263 mol) over20 min. The mixture was stirred and heated to 90° C. for 5 h. Themixture was cooled to rt and poured to iced water. The resultant mixturewas neutralized to pH 9 with saturated aq. NaOH (10 mL) and extractedwith EtOAc (2×100 mL). The organic layer was washed with brine (100 mL),filtered, dried (Na₂SO₄), filtered, and concentrated under reducedpressure to provide the title compound (7 g, 22%). The title compoundwas used crude in the next step without further purification. ¹H NMR(400 MHz, CDCl₃) δ 9.93 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 4.12 (s,3H).

Intermediate 28. 5-(3-Chlorophenyl)-6-methoxynicotinaldehyde

The title compound was prepared in a manner analogous to Intermediate 1,Step 3, employing 5-bromo-6-methoxynicotinaldehyde and3-chlorophenylboronic acid in THF/water, at 75° C. under N₂ overnight.¹H NMR (400 MHz, CDCl₃) δ 10.03 (s, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.09(d, J=2.4 Hz, 1H), 7.57, (d, J=0.88 Hz, 1H), 7.42-7.46 (m, 1H),7.36-7.41 (m, 2H), 4.09 (s, 3H).

Intermediate 29. (5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methanol

To a solution of 5-(3-chlorophenyl)-6-methoxynicotinaldehyde (18 g,0.072 mol) in EtOH (150 mL) was added NaBH₄ (5.5 g, 0.144 mol) at 0° C.The reaction mixture was stirred at room temperature under N₂ for 2 h.To the mixture was added HCl (1 M, 5 mL) dropwise, followed by water(100 mL) at 0° C. The mixture was extracted with EtOAc (2×100 mL). Theorganic layers were combined, washed with brine (100 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordthe title compound (16.2 g, 90%) as a yellow solid, which was used fornext step without further purified.

Intermediate 30. 5-(Chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine

The title compound was prepared in a manner analogous to Intermediate17, employing (5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methanol. ¹H NMR(400 MHz, CDCl₃) δ 8.17 (d, J=2.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H),7.55-7.66 (d, J=2.0 Hz, 1H) 7.35-7.44 (m, 3H), 4.61 (s, 2H), 3.99 (s,3H).

Intermediate 31.3-(3-Chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine

The title compound was prepared in a manner analogous to Intermediate 9,employing 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine,substituting K₂CO₃ and Pd(PPh₃)₄ (114 mg, 0.10 mmol) for potassiumacetate and Pd(dppf)Cl₂. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=2.35 Hz,1H), 7.55 (t, J=1.76 Hz, 1H), 7.42-7.47 (m, 2H), 7.29-7.37 (m, 2H), 3.95(s, 3H), 2.24 (s, 2H), 1.26 (s, 12H).

Intermediate 32.3-Bromo-2-ethoxy-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine

A solution of 3-bromo-5-(chloromethyl)-2-ethoxypyridine (2.84 g, 11.34mmol), NaI (169.93 mg, 1.13 mmol), K₂CO₃ (3.13 g, 22.67 mmol) and5-methyl-2H-tetrazole (1.91 g, 22.67 mmol) in ACN (50 mL) was stirred atrt for 72 h. The reaction mixture was filtered and concentrated underreduced pressure. Purification (FCC, SiO₂, hexanes/EtOAc, 0-100%)provided the title compound as an oil (1.83 g, 54%). ¹H NMR (400 MHz,CDCl₃) δ 8.04 (d, J=2.35 Hz, 1H), 7.74 (d, J=2.35 Hz, 1H), 5.40 (s, 2H),4.44 (q, J=7.04 Hz, 2H), 2.54 (s, 3H), 1.43 (t, J=7.04 Hz, 3H).

Intermediate 33. Ethyl2-(2-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)acetate

The title compound was prepared in a manner analogous to Intermediate32, with the appropriate starting material substitutions. ¹H NMR (400MHz, CDCl₃) δ 8.16 (d, J=2.35 Hz, 1H), 7.55 (d, J=2.35 Hz, 1H),7.50-7.52 (m, 1H), 7.34-7.38 (m, 3H), 5.59 (s, 2H), 4.20 (q, J=7.30 Hz,2H), 4.00 (s, 3H), 3.97 (s, 2H), 1.27 (t, J=7.24 Hz, 3H).

Intermediate 34.3-Bromo-2-ethoxy-5-((5-methyl-2H-tetrazol-2-yl)methyl)pyridine

Isolated from Intermediate 32 reaction. White solid (1.32 g, 39%) ¹H NMR(400 MHz, CDCl₃) δ 8.16 (d, J=2.35 Hz, 1H), 7.87 (d, J=1.96 Hz, 1H),5.61 (s, 2H), 4.44 (q, J=7.04 Hz, 2H), 2.53 (s, 3H), 1.39-1.49 (m, 3H).

Intermediate 35.(1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazol-4-yl)methanol

Step 1.1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde.3-Bromo-5-(chloromethyl)-2-methoxypyridine (Intermediate 25, 630 mg,2.66 mmol) in acetone (10 mL) was added Cs₂CO₃ (1.32 g, 4.0 mmol) andNaI (39.93 mg, 0.27 mmol). The reaction mixture was allowed to stir for3 h. The mixture was diluted with DCM and filtered. The filtrate wasdried (Na₂SO₄), filtered, and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 20-100%, EtOAc/hexanes) afforded thetitle compound as which was directly taken into the next step.

Step 2.(1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazol-4-yl)methanol.1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde(347 mg, 1.12 mmol) in MeOH (5 mL) was added NaBH₄ (42.33 mg, 1.22mmol). The reaction mixture was allowed to stir at room temperature for0.5 h. The mixture was diluted with water and extracted into DCM. Theorganic fractions were dried (Na₂SO₄), filtered, and the solvent wasremoved under reduced pressure. Purification (FCC, SiO₂, 50-100%,EtOAc/hexanes) afforded the title compound.

Intermediate 36.1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine

Step 1.3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine. Thetitle compound was prepared in a manner analogous to Intermediate 5 withthe appropriate starting material substitutions.

Step 2.1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine. To asolution of3-bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (1.0g, 3.18 mmol) in AcOH (15 mL), and water (4 mL) was added zinc (2.07 g,31.8 mmol). The mixture was stirred at 50° C. for 1 hr. The solvent wasremoved under reduced pressure to afford a white solid. The crude solidwas dissolved in DCM (50 mL), sonicated and filtered (repeated twice).The combined DCM extracts were washed with sat. aq. NaHCO₃ and thelayers separated. The organic layers were combined, dried (Na₂SO₄) andconcentrated under reduced pressure. The resulting solid was trituratedwith hexanes to give the title compound.

Intermediate 37.5-(Chloromethyl)-2-methoxy-[3,4′-bipyridine]-2′-carbonitrile

Step 1. 2′-Chloro-2-methoxy-[3,4′-bipyridine]-5-carbaldehyde. The titlecompound was prepared in a manner analogous to Intermediate 8 Step 3,employing 5-bromo-6-methoxynicotinaldehyde (Intermediate 27) and(2-chloropyridin-4-yl)boronic acid. [M+H]=249.25.

Step 2. 5-Formyl-2-methoxy-[3,4′-bipyridine]-2′-carbonitrile. Into a 10mL microwave vial were added2′-chloro-2-methoxy-[3,4′-bipyridine]-5-carbaldehyde (684 mg, 2.75mmol), dicyanozinc (226 mg, 1.93 mmol), Pd(PPh₃)₄ (318 mg, 0.28 mmol),and DMF (15 mL). The vial was capped, purged with nitrogen, then heatedat 150° C. for 15 min. The reaction mixture was diluted with EtOAc andextracted with water. The remaining organic phase was treated withbrine, dried (NaSO₄), filtered and concentrated. Purification (FCC,SiO₂, 0-75% EtOAc/hexanes) afforded the title compound (602.00 mg, 91%).[M+H]=240.28.

Step 3. 5-(Hydroxymethyl)-2-methoxy-[3,4′-bipyridine]-2′-carbonitrile.Into a 100 mL round bottomed flask containing5-formyl-2-methoxy-[3,4′-bipyridine]-2′-carbonitrile (602 mg, 2.52 mmol)was added MeOH (25 mL) followed by NaBH₄ (95 mg, 2.52 mmol). The rxnmixture was stirred at rt for 10 min. The reaction was was quenched withHCl (1 mL), then concentrated. The residue was diluted with sat. aq.NaHCO₃ and EtOAc. The layers were separated, and the organic phase wasextracted with EtOAc. The combined organic phase was dried (Na₂SO₄),filtered and concentrated to afford the title compound (219 mg, 36%) asa white solid. The crude material was used without further purification.[M+H]=242.30.

Step 4. 5-(Chloromethyl)-2-methoxy-[3,4′-bipyridine]-2′-carbonitrile. Toa solution of5-(hydroxymethyl)-2-methoxy-[3,4′-bipyridine]-2′-carbonitrile (219.3 mg,0.91 mmol) in DCM (10 mL) was added thionyl chloride (130 μL, 1.82mmol). The reaction mixture was stirred at rt for 2.5 h thenconcentrated to afford the title compound as a yellow solid (0.2225 g,94%). [M+H]=260.27.

Intermediate 38. 5-(Chloromethyl)-2′-ethoxy-2-methoxy-3,4′-bipyridine

Step 1. (2′-chloro-2-methoxy-[3,4′-bipyridin]-5-yl)methanol. The titlecompound was prepared in a manner analogous to Intermediate 8, Step 3,employing (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23) and(2-chloropyridin-4-yl)boronic acid. [M+H]=251.30.

Step 2. (2′-Ethoxy-2-methoxy-[3,4′-bipyridin]-5-yl)methanol. A solutionof (2′-chloro-2-methoxy-[3,4′-bipyridin]-5-yl)methanol (925 mg, 3.69mmol) in 21% w/w NaOEt in EtOH (22 mL) was heated at 75° C. for 8 hunder nitrogen. The rxn mixture was cooled to rt, diluted with EtOAc,washed with 1M citric acid (2×), dried (Na₂SO₄), filtered andconcentrated. Purification (FCC, SiO₂, 0-75% EtOAc/hexanes afforded(0.499 g, 52%) of the title compound as an amber oil. [M+H]=261.39.

Step 3. 5-(Chloromethyl)-2′-ethoxy-2-methoxy-3,4′-bipyridine. A solutionof (2′-ethoxy-2-methoxy-[3,4′-bipyridin]-5-yl)methanol (499.30 mg, 1.92mmol) in DCM (10 mL) and tetrahydrofuran (5 mL) was cooled in anice-water bath for 5 min. Thionyl chloride (0.35 mL, 4.8 mmol) was addeddropwise over 1 min. A white ppt formed immediately. The rxn mixture wasstirred for 1 h at rt, then quenched with sat. aq. NaHCO₃. The layerswere separated, and the aq. phase was extracted with DCM. The combinedorganic phase was dried (NaSO₄), filtered and concentrated to give (543mg, 101%) of the title compound as an amber oil. [M+H]=278.38.

Intermediate 39.5-(Chloromethyl)-2-(2,2-difluoroethoxy)-2′-ethoxy-3,4′-bipyridine

The title compound was prepared in a manner analogous to Intermediate38, employing (5-bromo-6-(2,2-difluoroethyoxy)pyridin-3-yl)methanol and(2-chloropyridin-4-yl)boronic acid in Step 1. [M+H]=329.37.

Intermediate 40.5-(Chloromethyl)-3-(3-chlorophenyl)-2-(2,2-difluoroethoxy)pyridine

The title compound was prepared in a manner analogous to Intermediate38, employing (5-bromo-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol and(2-chlorophenyl)boronic acid in Step 1. [M+H]=318.30.

Intermediate 41.5-(Chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine

Step 1. Methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate. To asolution of methyl 5-bromo-6-chloronicotinate (3.00 g, 11.98 mmol) inTHF (5 mL) was added 2,2,2-trifluoroethanol (1.44 g, 14.37 mmol). Thesolution was cooled in an ice-water bath under nitrogen for 5 minutes,then potassium tert-butoxide (12.58 mL, 1.00 mol/L, 12.58 mmol) wasadded dropwise over 5 minutes. The reaction mixture was stirred for 16h, then diluted with NaHCO₃ and EtOAc. The layers were separated, andthe organic phase was washed with water, and brine. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification (FCC, SiO₂, 0-15% EtOAc/hexanes) afforded thetitle compound (2.355 g, 63%) as a white solid. [M+H]=314.22/317.22.

Step 2. (5-Bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol. To acooled solution, 0° C., of 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate(2.36 g, 7.50 mmol) in THF (20 mL) under nitrogen, was added DIBAL(15.00 mL, 1.00 mol/L, 15.00 mmol) over 2 min. The reaction mixture wasallowed to warm to rt where it was stirred for 8 h. The rxn mixture wasconcentrated then diluted with DCM and stirred 48 h with 1M NaOH (25mL). The layers were separated, and the aq. phase was extracted withDCM. The combined organic phase was dried (Na₂SO₄), filtered, andconcentrated to yield (2.778 g, 130%) of the title compound as acolorless oil. [M+H]=286.23/288.23.

Step 3.(5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol. To asolution of (5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol(1.50 g, 5.24 mmol) in ACN (10.0 mL) was added 3-chloro-phenyl-boronicacid (902.02 mg, 5.77 mmol), Pd(dppf)Cl₂.DCM (42.82 mg, 0.05 mmol), and2 M aq. Na₂CO₃ (10.0 mL). The reaction mix was purged with nitrogen andheated under microwave irradiation for 30 min at 100° C. The layers wereseparated, and the aqueous phase was extracted with EtOAc. Purification(FCC, SiO₂, 0-50% EtOAc/hexanes) provided the title compound (1.0937 g,6₆) as an amber oil. [M+H]=318.30.

Step 4.5-(Chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine.To a cooled, 0° C., solution of(5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.09g, 3.4 mmol) in DCM (15.0 mL), was added thionyl chloride (0.63 mL, 8.6mmol) dropwise over 1 min. A white ppt formed immediately. Afterstirring 1 h at rt, more thionyl chloride (300 μL) was added, and thereaction mixture was stirred for additional 8 h. The reaction wasquenched with sat. aq. NaHCO₃, the layers were separated, and the aq.phase was extracted with DCM. The combined organic phase was dried(NaSO₄), filtered and concentrated to afford (0.9143 g, 79%) of thetitle compound as an amber oil. [M+H]=336.24.

Intermediate 42.5-(Chloromethyl)-2′-(difluoromethoxy)-2-methoxy-3,4′-bipyridine

The title compound was prepared in a manner analogous to Intermediate38, Steps 1 and Step 3, employing2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineand (5-bromo-6-methoxypyridin-3-yl)methanol (Intermediate 23) in Step 1.[M+H]=301.04.

Intermediate 43.5-(Chloromethyl)-2′-(difluoromethoxy)-2-ethoxy-3,4′-bipyridine

The title compound was prepared in a manner analogous to Intermediate38. [M+H]=315.05.

Intermediate 44. Methyl5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate

Step 1.5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile.The title compound was prepared analogous to Intermediate 7, Step 1,employing 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine(Intermediate 30) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile,and substituting Pd(PPh₃)₄ for Pd(dppf)Cl₂.DCM. [M+H]=337.34.

Step 2. Methyl5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate.To a cooled, 0° C., solution of wet MeOH was added acetyl chloride (2.0mL) dropwise over 5 min. The reaction mix was stirred an additional 35min. at 0° C., then added to5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile(278.4 mg, 0.83 mmol). The reaction mix was heated to 50° C. for 2.5 h.The rxn mixture was concentrated, diluted with EtOAc, neutralized withsat. aq. NaHCO₃. The layers organic phase was separated, washed withbrine, dried (Na₂SO₄), filtered and concentrated under reduced pressureto afford (277.5 mg, 91%) of the title compound as a colorless oil thatcontains some of the corresponding carboxylic acid. The title compoundwas used crude in the next step. [M+H]=370.37.

Intermediate 45. Methyl5-((2-(2,2-difluoroethoxy)-2′-ethoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoropicolinate

Prepared in the same manner as Intermediate 44 using intermediateIntermediate 39. [M+H]=448.39.

Intermediate 46. 5-(Bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine

The title compound was prepared in a manner analogous to Intermediate 1.

Intermediate 47. 5-(Chloromethyl)-3-(4-fluorophenyl)-2-methoxypyridine.

The title compound was prepared in a manner analogous to Intermediate17, employing (5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methanol.

Intermediate 48.2-Chloro-5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine

The title compound was prepared in a manner analogous to Intermediate 1,Step 3, employing5-(bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine (Intermediate46) and (2-chloropyrimidin-5-yl)boronic acid, substituting aq. NaHCO₃for Na₂CO₃. ¹H NMR (400 MHz, CDCl₃) d 8.66 (s, 2H), 7.98-8.05 (m, 2H),7.87-7.93 (m, 1H), 7.20-7.26 (m, 1H), 4.50 (q, J=7.04 Hz, 2H), 4.10 (s,2H), 1.47 (t, J=7.04 Hz, 3H). [M+H]=363.4.

Intermediate 49. Ethyl2-(4-{[5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate

The title compound was prepared in a manner analogous to Intermediate24, employing 5-(chloromethyl)-3-(3,4-difluorophenyl)-2-methoxypyridineand (4-(2-ethoxy-2-oxoethyl)phenyl)boronic acid. [M+H]=398.41.

Intermediate 50. Ethyl2-(4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetate

The title compound was prepared in a manner analogous to Intermediate24, employing Intermediate 30 and (4-(2-ethoxy-2-oxoethyl)phenyl)boronicacid. [M+H]=396.32.

Intermediate 51.2-Chloro-5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine

The title compound was prepared in a manner analogous to Intermediate24, employing Intermediate 47 and (2-chloropyrimidin-5-yl)boronic acid.[M+H]=330.40.

Intermediate 52.5-((5-Bromo-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Intermediate21, from 3-bromo-5-(chloromethyl)-2-ethoxypyridine (Intermediate 17) and2-aminopyrimidine-5-boronic acid.

Intermediate 53.2-(5-((5-(4-Fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile

The title compound was prepared in a manner analogous to Intermediate 7,from 5-(chloromethyl)-3-(4-fluorophenyl)-2-methoxypyridine (Intermediate47) and2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetonitrile.

Intermediate 54.2-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile

The title compound was prepared in a manner analogous to Intermediate10, Step 1, employing Intermediate 30 and2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)acetonitrile,omitting water as a co-colvent.

Intermediate 55. tert-Butyl(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate

A solution of3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine(Intermediate 31, 127.7 mg, 0.36 mmol), tert-butyl(5-bromopyrazin-2-yl)carbamate (126.53 mg, 0.46 mmol), K₂CO₃ (98 mg,0.70 mmol) and Pd(PPh₃)₄ (32.8 mg, 0.03 mmol) in dioxane (3.00 mL) andwater (600.00 μl) was heated at 110° C. overnight.

Intermediate 56. tert-Butyl(5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate

The title compound was prepared in a manner analogous to Intermediate21, employing3-(3-chloro-4-fluorophenyl)-5-(chloromethyl)-2-methoxypyridine(Intermediate 26) and tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-yl) carbamate.

Intermediate 57.2-Bromo-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazine

The title compound was prepared in a manner analogous to Intermediate55, employing3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine(Intermediate 31) and 2-bromo-5-iodopyrazine. ¹H NMR (400 MHz, CDCl₃) δ8.62 (d, J=1.57 Hz, 1H), 8.29 (d, J=0.78 Hz, 1H), 8.10 (d, J=2.35 Hz,1H), 7.47-7.56 (m, 2H), 7.31-7.43 (m, 3H), 4.10 (s, 2H), 3.97 (s, 3H).

Intermediate 58.5-((6-Chloro-5-fluoropyridin-3-yl)methyl)-2′-(difluoromethoxy)-2-methoxy-3,4′-bipyridine

The title compound was prepared in a manner analogous to Intermediate 1,using Intermediate 39, employing microwave heating, substituting sodiumbicarbonate for sodium carbonate.

EXAMPLES Example 1.5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile

Into a 5 mL microwave vial was combined5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine(Intermediate 1, 176.00 mg, 0.49 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile(124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), Pd(PPh₃)₄(56.63 mg, 0.05 mmol), and aq. NaHCO₃ (1.38 mL, 1.15 mol/L, 1.59 mmol).The vial was sealed, purged with nitrogen and heated to 125° C. undermicrowave conditions for 15 minutes. Water was removed from the reactionwith a pipette, and the crude reaction mixture was filtered thruCELITE®, and washed with EtOAc (3×5 mL). The combined organic layerswere dried (Na₂SO₄), and the solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-30%, EtOAc/hexanes) afforded the titlecompound as a white solid (100 mg, 53%). ¹H NMR (400 MHz, CD₃OD) δ 8.94(s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46(t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49(q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H).[M+H]=384.15.

Example 2.2-Chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine

To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine(Intermediate 2, 100 mg, 0.321 mmol), (2-chloropyrimidin-5-yl)boronicacid (76 mg, 0.481 mmol) in ACN (3.2 mL) was added NaHCO₃ (417 mg, 1.282mmol) and PdCI₂(dppf)-DCM (23 mg, 0.032 mmol). The reaction was heatedunder microwave conditions, at 120° C. for 12 minutes. Water was removedfrom the reaction with a pipette, and the crude reaction mix wasfiltered thru CELITE®, and washed with EtOAc. The combined organics weredried (Na₂SO₄), filtered and concentrated onto silica. Purification(FCC, SiO₂, 30-70% EtOAc/hexanes) afforded the title compound (61 mg,55%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H),7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 3.83(s 2H), 3.73 (s, 3H). [M+H]=346.11.

Example 3.{2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethyl}dimethylamine

To a solution of2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine(Example 2, 50.00 mg, 0.14 mmol) in ACN (1.44 mL), was addedN1,N1-dimethylethane-1,2-diamine (0.03 mL, 0.29 mmol), and DIPEA (77.13μL, 0.43 mmol). The reaction mixture was heated at 180° C. for 15minutes. EtOAc (5 mL) was added to the reaction mixture, and thereaction mixture was extracted with water (3×). The combined organiclayers were dried (Na₂SO₄), and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 0-15% MeOH/DCM) afforded the titlecompound (15.6 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 2H), 8.09(s, 1H), 7.67 (br s, 2H), 7.58 (s, 1H), 7.51-7.34 (m, 2H), 6.79 (br s,1H), 3.84 (s, 3H), 3.72 (s, 2H), 2.42-2.37 (m, 4H), 2.17 (s, 6H).[M+H]=398.20.

Example 4.2-Methoxy-3-(6-methoxypyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

A solution of5-((1H-1,2,4-triazol-1-yl)methyl)-3-bromo-2-(difluoromethoxy)pyridine(Intermediate 13, 50 mg, 0.16 mmol), (6-methoxypyridin-2-yl)boronic acid(46 mg, 0.30 mmol), in EtOH (2.45 mL), benzene (7.00 mL), was combinedwith Pd(PPh₃)₄ (27 mg, 0.02 mmol), and 4 M aq. Na₂CO₃ (3 mL) in amicrowave vial. The vial was sealed, purged with nitrogen and heatedunder microwave conditions to 120° C. for 12 minutes. Water was removedfrom the reaction with a pipette, and the crude reaction mix wasfiltered thru CELITE®, and washed with EtOAc (3×5 mL). The combinedorganic layers were dried (Na₂SO₄), and the solvent was removed underreduced pressure. Purification (FCC, SiO₂, 30-70% EtOAc/hexanes)afforded the title compound (11.9 mg, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ7.88 (s, 1H), 7.58 (d, J=2.7 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.24 (s,1H), 6.91-6.84 (m, 2H), 5.93 (d, J=4.3 Hz, 1H), 4.69 (s, 2H), 3.97 (s,3H), 3.14 (s, 3H). [M+H]=298.02.

Examples 5-12 were prepared analogous to procedures described inExamples 1 or 2, with the appropriate starting materials and reagentsubstitutions.

Example 5.2-Methoxy-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.18-8.15 (m, 1H), 7.95 (s,1H), 7.70 (d, J=2.3 Hz, 1H), 7.31-7.27 (m, 3H), 7.19-7.14 (m, 1H), 5.41(s, 2H), 3.85 (s, 3H), 2.33 (s, 3H). [M+H]=281.36.

Example 6.2-Methoxy-3-(5-methylpyridin-3-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.77 (s, 2H), 8.57 (s, 1H),8.35 (d, J=2.0 Hz, 1H), 8.04 (s, 2H), 5.45 (s, 2H), 3.91 (s, 3H), 2.50(s, 3H). [M+H]=282.09.

Example 7.2-Methoxy-3-(2-methylpyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.77-8.63 (m, 2H), 8.37 (d, J=2.3 Hz, 1H),8.04 (d, J=2.0 Hz, 1H), 8.00-7.85 (m, 2H), 7.58-7.43 (m, 1H), 5.45 (s,2H), 3.92 (s, 3H), 2.68 (s, 3H). [M+H]=282.20.

Example 8.{3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]phenyl}methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.95(s, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.45-7.26 (m, 4H), 5.41 (s, 2H), 5.22(t, J=5.7 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 3.85 (s, 3H). [M+H]=297.23.

Example 9.3-(3-Methanesulfonylphenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.24 (d, J=1.96 Hz, 1H), 8.12(s, 1H), 8.00 (s, 1H), 7.94 (d, J=7.83 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H),7.83 (d, J=1.56 Hz, 1H), 7.65-7.72 (m, 1H), 5.46 (s, 2H), 3.96 (s, 3H),3.15 (s, 3H). [M+H]=345.21.

Example 10.2-Methoxy-3-(4-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.26 (d,J=2.3 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.98 (s, 1H), 7.70 (s, 1H), 7.22(d, J=5.1 Hz, 1H), 5.46 (s, 2H), 3.99 (s, 3H), 2.42 (s, 3H).[M+H]=282.31.

Example 11.2-Methoxy-3-(6-methylpyridin-2-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.32-8.27 (m, 1H), 8.22 (d,J=2.3 Hz, 1H), 7.89 (s, 1H), 7.68-7.62 (m, 1H), 7.56 (d, J=2.7 Hz, 1H),7.26 (dd, J=5.1, 7.8 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 3H), 2.04 (s, 3H).[M+H]=282.39.

Example 12.2-(Difluoromethoxy)-3-(3-methylphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

As a mixture of compounds, ¹H NMR (400 MHz, DMSO-d₆) δ 8.72-8.61 (m,1H), 8.00-7.96 (m, 1H), 7.94-7.86 (m, 1H), 7.73-7.68 (m, 1H), 7.55-7.51(m, 1H), 7.40-7.33 (m, 1H), 7.32-7.27 (m, 1H), 7.24 (d, J=7.8 Hz, 1H),5.75 (s, 1H), 5.49 (s, 1H), 5.44 (s, 1H), 2.35 (s, 3H). [M+H]=317.15.

Example 13.5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide

To a solution of5-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine-2-carbonitrile(Example 1, 100.00 mg, 0.26 mmol) in MeOH (1.3 mL) was added aq. NaOH(0.78 mL, 0.78 mmol), followed by H₂O₂(0.78 mL, 0.79 mmol). The reactionmixture was stirred at rt for 8 h. The reaction mixture wasconcentrated, and the precipitate filtered and washed with water toobtain the title compound as a white solid (70 mg, 67%). ¹H NMR (400MHz, DMSO-d₆) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.91-7.84(m, 1H), 7.81 (t, J=1.8 Hz, 1H), 7.72 (br s, 1H), 7.52 (s, 1H),7.44-7.02 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.35 (t, J=7.0Hz, 3H). [M+H]=402.26.

Example 14.[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol

To a cooled solution, −78° C., of5-bromo-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 7, 1.5 g, 5mmol) in THF (25 mL), under nitrogen, was added nBuLi (4.8 mL, 5.5 mmol)drop-wise over 2 minutes. The reaction mixture was stirred at −78° C.for 40 min. A solution of 4-fluorobenzaldehyde (744 mg, 6 mmol) in THF(2 mL) was added, and the reaction mixture was stirred an additional 30min at −78° C. The reaction was quenched with sat. Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-25%EtOAc/hexanes) afforded the title compound as a colorless solid (1.65 g,96%). ¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=2.3 Hz, 1H), 7.63 (d, J=2.0Hz, 1H), 7.51 (s, 1H), 7.47-7.29 (m, 5H), 7.07 (t, J=8.6 Hz, 2H), 5.84(s, 1H), 3.93 (s, 3H). [M+H]=344.18.

Examples 15-16 were prepared in a manner analogous to Example 14, withthe appropriate starting materials and reagent substitutions.

Example 15.1-[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]-1-(4-fluorophenyl)ethan-1-ol

¹H NMR (400 MHz, CD₃OD) δ 8.16 (d, J=2.7 Hz, 1H), 7.68 (d, J=2.7 Hz,1H), 7.53-7.43 (m, 3H), 7.42-7.28 (m, 3H), 7.04 (t, J=8.8 Hz, 2H), 3.93(s, 3H), 1.94 (s, 3H). [M+H]=358.21.

Example 16.[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](5-fluoropyridin-2-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, J=2.7 Hz, 1H), 8.16 (d, J=2.3 Hz,1H), 7.77-7.58 (m, 3H), 7.52 (s, 1H), 7.45-7.28 (m, 3H), 5.87 (s, 1H),3.93 (s, 3H). [M+H]=345.19.

Example 17.{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine

Step 1.5-(Chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine.To a cooled solution, 0° C., of[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol(Example 14, 1.43 g, 4.17 mmol), in DCM (10 mL), was added thionylchloride (744 mg, 6.25 mmol) dropwise. The solution was allowed to warmup to room temperature, and stirred for 1 h. The reaction mixture wasconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-10%EtOAc/hexanes) afforded the title compound, which was used directly forthe next step.

Step 2.{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}(methyl)amine.To a solution of5-(chloro(4-fluorophenyl)methyl)-3-(3-chlorophenyl)-2-methoxypyridine(70 mg, 0.193 mmol) in ACN (2 mL) was added K₂CO₃ (53 mg, 0.39 mmol),NaI (5 mg, 0.03 mmol), and methylamine (0.5 mL, 0.97 mmol). The reactionwas sealed and heated at 45° C. for 12 h. The reaction mixture wasconcentrated. Purification (FCC, SiO₂, 0-10% MeOH/DCM) afforded thetitle compound (23 mg, 33%). ¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J=2.3Hz, 1H), 7.71 (s, 1H), 7.50-7.42 (m, 3H), 7.40-7.27 (m, 3H), 7.18 (t,J=8.8 Hz, 2H), 5.54-5.49 (m, 1H), 3.90 (s, 3H), 2.63 (s, 3H). [M⁺; lossof NHMe]=326.14.

Examples 18-19 were prepared in a manner analogous to Example 17, withthe appropriate starting materials and reagent substitutions.

Example 18.[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanamine

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J=2.3 Hz, 1H), 7.72 (d, J=2.7 Hz,1H), 7.55 (s, 1H), 7.49-7.34 (m, 5H), 7.18 (m, 2H), 5.58 (s, 1H), 3.96(s, 3H). [M⁺; loss of NH₂]=326.14.

Example 19.{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methyl}dimethylamine

¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J=2.3 Hz, 1H), 7.86 (s, 1H), 7.57(dd, J=5.1, 8.6 Hz, 2H), 7.50 (t, J=1.6 Hz, 1H), 7.43-7.28 (m, 3H), 7.18(m, 2H), 5.51-5.38 (m, 1H), 3.90 (s, 3H), 2.88-2.74 (m, 6H).[M+H]=371.20.

Example 20.3-(3-Chlorophenyl)-5-[fluoro(4-fluorophenyl)methyl]-2-methoxypyridine

To a solution of[5-(3-chlorophenyl)-6-methoxypyridin-3-yl](4-fluorophenyl)methanol(Example 14, 70 mg, 0.18 mmol) in DCM (1 mL) was added Deoxo-Fluor® (79mg, 0.36 mmol). The solution was stirred at room temperature for 1 hthen concentrated under reduced pressure. Purification (FCC, SiO₂, 0-10%EtOAc/hexanes) afforded the title compound (21 mg, 34%). ¹H NMR (400MHz, CD₃OD) δ 8.13 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.52 (s, 1H),7.47-7.31 (m, 5H), 7.15 (t, J=8.8 Hz, 2H), 6.70-6.52 (m, 1H), 3.96 (s,3H). [M+H]=346.17.

Example 21. 4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoicacid

Step 1. Methyl4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate wasprepared in a manner analogous to Example 2 with the appropriatestarting material substitution. Purification (FCC, SiO₂, 0-50%EtOAc/hexanes) afforded the title compound. [M+H]=368.11 Step 2.4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzoic acid. To asolution of methyl4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoate (91 mg,0.248 mmol) in MeOH (2 mL) was added 2 N aq. NaOH (2.0 mL). The reactionmixture was stirred at rt for 2 h. Solvent was removed under reducedpressure, and the resulting solid was triturated with diethyl ether. Theresulting white solid was dissolved in DCM and filtered to removeinorganic solids. The filtrated was concentrated under reduced pressureto afford the title compound (74 mg, 85%). ¹H NMR (400 MHz, CD₃OD) δ8.03 (d, J=2.0 Hz, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.60 (d, J=2.3 Hz, 1H),7.52 (s, 1H), 7.43-7.30 (m, 5H), 4.05 (s, 2H), 3.95 (s, 3H).[M+H]=354.13.

Example 22.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile

Example 22 was prepared in a manner analogous to Example 1, with theappropriate starting materials and reagent substitutions. [M+H]=338.10

Example 23.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylicacid

A solution of5-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile(Example 22, 30 mg, 0.0845 mmol) in MeOH (1.54 mL) was heated to 50° C.until the starting material dissolved. 1 N aq. NaOH (0.23 mL, 0.23 mmol)was added followed by H₂O₂ (0.23 mL, 1.00 mol/L, 0.23 mmol) and thesolution was heated at 50° C. for an additional 2 h. Water (5 mL) wasadded and the reaction was filtered and washed with water (3×5 mL). Amixture of products were observed;5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxylicacid (the title compound) and5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide(Example 24, 4 mg, 13%). The filtrated contained the acid, and the waterlayer was acidified with concentrated HCl (3 drops) and extracted withDCM (3×20 mL). The organic layers were combined, dried (Na₂SO₄), andconcentrated under reduced pressure to afford the title compound (23 mg,74%). ¹H NMR (400 MHz, CD₃OD) δ 8.86 (br s, 2H), 8.11 (d, J=1.96 Hz,1H), 7.66 (d, J=1.96 Hz, 1H), 7.55 (s, 1H), 7.49-7.27 (m, 3H), 4.14 (brs, 2H), 3.94 (s, 3H). [M+H]=356.13 Example 24.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide.

The title compound was made in a manner analogous to Example 13. ¹H NMR(400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.65 (d, J=2.3Hz, 1H), 7.54 (s, 1H), 7.47-7.29 (m, 3H), 4.12 (s, 2H), 3.94 (s, 3H).[M+H]=355.21.

Examples 25, 27-30, 32-35, 37-43, 45-89, 91-108 were prepared analogousto procedures described in Examples 1 or 2, with the appropriatestarting materials and reagent substitutions.

Example 25.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 8.02 (d, J=2.3 Hz, 1H),7.58-7.51 (m, 2H), 7.44-7.31 (m, 3H), 3.93 (s, 3H), 3.82 (s, 2H).[M+H]=327.21.

Example 26.(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea

Step 1. 3-(3-Chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine. Thetitle compound was prepared in a manner analogous to Example 1, fromIntermediate 2 and 4-nitrophenyl boronic acid to afford a tan solid.[M+H]=355.07.

Step 2. 4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline. Asolution of 3-(3-chlorophenyl)-2-methoxy-5-(4-nitrobenzyl)pyridine (162mg, 0.45 mmol), HOAc (3 mL), water (1 mL), and zinc (292.5 mg, 4.5 mmol)was heated at 60° C. for 1 h, then filtered hot through a 1 cm pad ofCelite® and used directly for the next step.

Step 3.(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)urea.4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)aniline solutionfrom Step 2 was added KCNO (73 mg, 0.9 mmol). The mixture was sonicatedfor 20 min to afford a gummy ppt. The reaction mixture was diluted withwater, neutralized with aq. Na₂CO₃ to pH 7, then extracted with EtOAc(3×5 mL). The combined organic layers were concentrated under reducedpressure to afford a solid, which was triturated with DCM to give (55mg, 34%) of the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.41 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.64-7.53 (m, 2H),7.49-7.37 (m, 3H), 7.28 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 5.75(s, 2H), 3.85-3.81 (m, 5H). [M+H]=368.27.

Example 27.4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.2 Hz,2H), 7.56-7.49 (m, 2H), 7.42-7.29 (m, 5H), 4.03 (s, 2H), 3.92 (s, 3H).[M+H]=353.13.

Example 28.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-pyrazol-4-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (br s, 1H), 7.92-7.43 (m, 9H), 3.84(s, 2H). [M+H]=336.18.

Example 29.5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 2H), 8.07 (d, J=2.35 Hz, 1H), 7.71(d, J=1.96 Hz, 1H), 7.57 (s, 1H), 7.30-7.38 (m, 1H), 7.02-7.10 (m, 2H),6.95 (dd, J=8.22, 1.57 Hz, 1H), 3.82 (s, 3H), 3.87 (s, 2H).[M+H]=359.28.

Example 30.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.0 Hz, 1H), 7.80 (d, J=2.0 Hz,1H), 7.52 (d, J=2.0 Hz, 2H), 7.43-7.29 (m, 4H), 6.55 (d, J=8.6 Hz, 1H),3.92 (s, 3H), 3.81 (s, 2H). [M+H]=326.26.

Example 31.1-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)-3-(oxetan-3-yl)urea

To a solution of4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)benzoic acid(Example 21, 90 mg, 0.25 mmol) in toluene (5 mL) was added DIPEA (33 mg,0.25 mmol) and DPPA (77 mg, 0.28 mmol). The mixture was stirred at 80°C. for 30 minutes. The LCMS confirmed the disappearance of the startingacid. A solution of oxetan-3-amine hydrochloride (41.5 mg, 0.38 mmol),DIPEA (49 mg, 0.38 mmol) and DCM (2 mL) was added to the reactionmixture and stirred at room temperature for 2 h. The LCMS confirmed thepresence of the product. All solvents were removed under reducedpressure. Purification (FCC, SiO₂, 0-5%, MeOH/DCM) afforded the titlecompound (50 mg, 46%). ¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H),7.49 (d, J=2.3 Hz, 2H), 7.41-7.24 (m, 5H), 7.14 (d, J=8.6 Hz, 2H), 4.87(br s, 3H), 4.55 (s, 2H), 3.91 (s, 3H), 3.90 (s, 2H). [M+H]=424.20.

Example 32.3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxypyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (dd, J=2.0, 6.3 Hz, 2H), 7.67 (d, J=2.3Hz, 1H), 7.61-7.54 (m, 2H), 7.50-7.36 (m, 3H), 6.72 (d, J=8.2 Hz, 1H),3.86 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). [M+H]=341.19.

Example 33.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.06 (d, J=2.3 Hz, 1H), 7.77 (dd, J=2.0, 9.4Hz, 1H), 7.73-7.64 (m, 2H), 7.51-7.30 (m, 5H), 6.89 (d, J=9.4 Hz, 1H),3.88 (s, 2H). [M+H]=362.31.

Example 34.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz,1H), 7.51 (d, J=1.6 Hz, 2H), 7.43-7.29 (m, 4H), 6.63 (d, J=9.0 Hz, 1H),3.92 (s, 3H), 3.84 (s, 2H), 3.04 (s, 6H). [M+H]=354.22.

Example 35.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.18 (s, 1H), 7.85 (d, J=2.3 Hz,1H), 7.80-7.38 (m, 5H), 4.21-4.17 (m, 2H). [M+H]=373.14.

Example 36.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine

Step 1. 3-(3-Chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridinewas prepared in a manner analogous to Intermediate 1, Steps 4, with theappropriate starting material substitutions. [M+H]=426.1, 428.1, 430.1.

Step 2. 5-(3-Chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde. To asolution of3-(3-chlorophenyl)-5-(dibromomethyl)-2-(difluoromethoxy)pyridine (700mg, 1.65 mmol) in ACN (2 mL) was added a solution of Na₂CO₃ (525 mg, 5.0mmol) in water (4 mL) and the mixture was stirred at 70° C. for 16 h.The LCMS showed complete conversion. All solvents were removed underreduced pressure. The residue was dissolved in DCM, washed with water,dried (Na₂SO₄), filtered and the solvent was removed under reducedpressure. Purification (FCC, SiO₂, 0-20%, EtOAc/hexanes) afforded5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (355 mg, 76%).[M+H]=284.1.

Step 3. tert-Butyl(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate.A solution of tert-butyl (5-bromothiazol-2-yl)carbamate (100 mg, 0.36mmol) in THF (2 mL) was cooled to −78° C. and n-butyllithium (0.51 mL of1.4 M solution in hexanes, 0.72 mmol) was added dropwise and the mixturewas stirred for 30 minutes at −78° C. A solution of5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde (112 mg, 0.39mmol) in THF (2 mL) was added dropwise to the reaction and this mixturewas stirred for 30 minutes at −78° C. The LCMS confirmed the product. Asaturated aqueous solution of ammonium chloride was added and themixture was extracted into EtOAc. The combined extracts were dried(Na₂SO₄), filtered and solvent was removed under reduced pressure.Purification (FCC, SiO₂, 10-80%, EtOAc/hexanes) afforded tert-butyl(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate(73 mg, 42%). [M(-tBu)+H]=428.1.

Step 4.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine.To a solution of tert-butyl(5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)(hydroxy)methyl)thiazol-2-yl)carbamate(73 mg, 0.15 mmol) in DCM (3 mL) was added TES (52.2 mg, 0.45 mmol) andTFA (102 mg, 0.90 mmol) and the mixture was stirred at room temperaturefor 16 h. The LCMS showed complete conversion. All solvents were removedin vacuo. The residue was dissolved in DCM and sat. aq. NaHCO₃, thelayers shaken and separated and the aqueous layer extracted into DCM.The combined organic extracts were washed with brine, dried (Na₂SO₄),filtered and solvent under reduced pressure. Purification (FCC, SiO₂,20-100%, EtOAc/hexanes) gave the title compound (34.4 mg, 62%). ¹H NMR(400 MHz, CD₃OD) δ 8.02 (d, J=2.3 Hz, 1H), 7.71-7.30 (m, 6H), 6.68 (s,1H), 3.94 (s, 2H). [M+H]=368.06.

Example 37.(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanol

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=2.3 Hz, 1H), 7.49 (m, 2H),7.44-7.14 (m, 7H), 4.63 (s, 2H), 4.07 (s, 2H), 3.91 (s, 3H).[M+H]=340.13.

Example 38.5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 2H), 8.02 (d, J=2.3 Hz, 1H), 7.57 (d,J=2.3 Hz, 1H), 7.43-7.25 (m, 3H), 7.09-7.02 (m, 1H), 3.93 (s, 3H), 3.81(s, 2H). [M+H]=311.00.

Example 39.5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CLOROFORM-d) δ 8.71 (s, 2H), 8.06 (d, J=2.3 Hz, 1H),7.55 (s, 1H), 7.42-7.35 (m, 2H), 7.26-7.23 (m, 1H), 7.10-7.03 (m, 1H),4.05 (s, 2H), 3.98 (s, 3H). [M+H]=321.17.

Example 40.5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 7.99 (d, J=2.3 Hz, 1H), 7.56 (d,J=2.3 Hz, 2H), 7.47-7.30 (m, 3H), 4.38 (d, J=7.0 Hz, 2H), 3.81 (s, 2H),1.33 (t, J=7.0 Hz, 3H). [M+H]=341.04.

Example 41.5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 2H), 8.01-7.98 (m, 1H), 7.58-7.53 (m,2H), 7.46-7.29 (m, 3H), 5.35 (m, 1H), 3.80 (s, 2H), 1.30 (d, J=6.3 Hz,6H). [M+H]=355.21.

Example 42.5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 2H), 8.06 (d, J=2.3 Hz, 1H),7.78-7.29 (m, 3H), 7.06-7.00 (m, 2H), 6.95-6.90 (m, 1H), 4.68-4.55 (m,1H), 3.86 (s, 2H), 1.32 (d, J=6.3 Hz, 6H). [M+H]=387.25.

Example 43.5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.10 (s, 2H), 7.99 (d, J=2.3 Hz, 1H),7.69-7.24 (m, 3H), 7.04-6.99 (m, 1H), 6.84-6.80 (m, 1H), 6.75-6.70 (m,1H), 5.21 (m, 1H), 4.92 (t, J=7.0 Hz, 2H), 4.64-4.59 (m, 2H), 3.78 (s,2H). [M+H]=401.22.

Example 44.N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

Step 1. To a solution of5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine(Example 25, 50.0 mg, 0.15 mmol), in DCM (10 mL), was added and DIPEA(40 mg, 0.31 mmol). The solution was cooled to 0° C. and acetyl chloride(230 μL, (0.23 mmol) was added dropwise. The reaction mixture wasallowed warm up to room temperature overnight, then concentrated toafford the corresponding imide (bis-acylated adduct), which was usedcrude in the next step.

Step 2.N-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide.A solution of the crude product from step 1 in added ammonia (7N inmethanol) was stirred at room temperature for 1 h. Purification (FCC,SiO₂, 0-100% EtOAc/hexanes) afforded the title compound (11.4 mg, 21%)as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.59(s, 2H), 8.14 (d, J=2.7 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.61-7.54 (m,1H), 7.51-7.38 (m, 3H), 3.90 (s, 2H), 3.85 (s, 3H), 2.12 (s, 3H).[M+H]=369.20.

Example 45.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methanesulfonylphenyl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.89 (d, J=8.2 Hz, 2H),7.78-7.37 (m, 8H), 4.16 (s, 2H), 3.08 (s, 3H). [M+H]=424.16.

Example 46.5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.27-8.16 (m, 4H), 7.85 (d, J=2.3 Hz, 1H),7.63 (t, J=1.0 Hz, 1H), 7.16-6.96 (m, 2H), 3.96 (s, 3H), 3.89 (s, 2H).[M+H]=360.23.

Example 47.5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.23-8.20 (m, 1H), 8.18 (s, 2H), 8.11 (d,J=2.3 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.56 (s, 1H), 7.41-7.36 (m, 1H),7.20-7.16 (m, 1H), 3.96 (s, 3H), 3.84 (s, 2H). [M+H]=360.23.

Example 48.2-[5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-yl]propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.63 (d,J=2.3 Hz, 1H), 7.46-7.35 (m, 2H), 7.31 (t, J=1.8 Hz, 1H), 7.12 (td,J=1.0, 7.4 Hz, 1H), 7.03-6.64 (m, 1H), 4.04 (s, 2H), 3.94 (s, 3H), 1.20(s, 6H). [M+H]=402.26.

Example 49.3-(3-Chlorophenyl)-2-methoxy-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.66 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.3 Hz,1H), 7.93-7.89 (m, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.62 (d, J=2.3 Hz, 1H),7.55 (t, J=1.6 Hz, 1H), 7.45-7.32 (m, 3H), 4.13 (s, 2H), 3.94 (s, 3H).[M+H]=379.15.

Example 50.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[6-(propan-2-yloxy)pyridin-3-yl]methyl}pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J=2.15, 10.37 Hz, 2H), 7.31-7.72 (m,7H), 6.64 (d, J=8.61 Hz, 1H), 5.27 (m, 1H), 3.90 (s, 2H), 1.34 (d,J=6.26 Hz, 6H). [M+H]=405.22.

Example 51.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-propoxypyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.06-8.00 (m, 2H), 7.71-7.31 (m, 7H), 6.70 (d,J=9.00 Hz, 1H), 4.23 (t, J=6.85 Hz, 2H), 3.91 (s, 2H), 1.80 (q, J=6.65Hz, 2H), 1.02 (t, J=7.43 Hz, 3H).

Example 52.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1-methyl-1,2-dihydropyridin-2-one

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=2.0 Hz, 1H), 7.60-7.51 (m, 3H),7.47-7.30 (m, 4H), 6.51 (d, J=9.4 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 2H),3.55 (s, 3H). [M+H]=341.19.

Example 53. 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-4-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=4.70 Hz, 1H), 8.12 (s, 1H), 7.71(s, 1H), 7.61-7.56 (m, 2H), 7.55-7.31 (m, 3H), 7.29 (d, J=4.70 Hz, 2H),3.96 (s, 2H), 3.85 (s, 3H). [M+H]=311.13.

Example 54.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxylicacid

Example 54 was prepared in a manner analogous to Example 21, with theappropriate starting materials and reagent substitutions. ¹H NMR (400MHz, DMSO-d₆) δ 8.61 (br s, 1H), 8.19 (br s, 1H), 8.12-7.94 (m, 1H),7.93-7.75 (m, 2H), 7.72-7.57 (m, 3H), 7.56-7.39 (m, 3H), 4.10 (br s,2H). [M+H]=391.25.

Example 55.3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine

¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 2H), 8.23 (s, 1H), 8.03-7.86 (m,2H), 7.50 (d, J=4.30 Hz, 2H), 4.09 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H).[M+H]=343.01.

Example 56.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.48 (br s, 1H), 8.13 (s, 2H), 8.07-7.90 (m,2H), 7.42 (d, J=5.09 Hz, 2H), 4.11-3.94 (m, 5H), 2.96 (s, 3H).[M+H]=342.05.

Example 57.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.18 (m, 1H), 7.93-8.05 (m, 2H),7.59-7.70 (m, 1H), 7.50-7.55 (m, 1H), 7.41 (d, J=5.09 Hz, 2H), 4.09 (s,2H), 4.03 (s, 3H), 2.68 (m, 1H), 0.84-0.97 (m, 2H), 0.61-0.71 (m, 2H).[M+H]=368.06.

Example 58.3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.10-7.92 (m, 3H), 7.55 (br s, 1H), 7.45-7.39(m, 3H), 4.01 (s, 3H), 3.98 (s, 2H), 3.83 (s, 3H). [M+H]=315.01.

Example 59.(4-{[5-3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)methanamine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=1.96 Hz, 2H), 7.47 (s, 2H),7.44-7.14 (m, 6H), 3.94 (s, 2H), 3.91 (s, 3H). [M+H]=339.10.

Example 60.4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=1.96 Hz, 1H), 7.81-7.74 (m, 1H),7.58-7.48 (m, 2H), 7.45-7.25 (m, 3H), 6.50 (d, J=5.48 Hz, 1H), 6.43 (s,1H), 3.93 (s, 3H), 3.85 (s, 2H). [M+H]=326.01.

Example 61.3-(3-Chlorophenyl)-5-[(2,6-dimethylpyridin-4-yl)methyl]-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=2.35 Hz, 1H), 7.59-7.48 (m, 2H),7.47-7.25 (m, 3H), 6.97 (s, 2H), 3.98-3.86 (m, 5H), 2.43 (s, 6H).[M+H]=339.05.

Example 62.4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J=5.09 Hz, 1H), 8.07 (d, J=2.35 Hz,1H), 7.79 (s, 1H), 7.60 (d, J=2.35 Hz, 1H), 7.54 (d, J=1.96 Hz, 2H),7.48-7.26 (m, 3H), 4.08 (s, 2H), 3.93 (s, 3H). [M+H]=336.14.

Example 63.4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide

The title compound was made in a manner analogous to Example 23, from4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carbonitrile(Example 62), reaction run at rt. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d,J=5.09 Hz, 1H), 8.15 (d, J=1.96 Hz, 1H), 8.05 (br s, 1H), 7.92 (s, 1H),7.74 (d, J=1.96 Hz, 1H), 7.58 (d, J=1.57 Hz, 2H), 7.54-7.33 (m, 4H),4.05 (s, 2H), 3.85 (s, 3H). [M+H]=354.15.

Example 64. 3-(3-Chlorophenyl)-2-methoxy-5-(pyridin-3-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J=2.0 Hz, 1H), 8.39 (dd, J=1.2, 4.7Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.70-7.66 (m,1H), 7.58 (d, J=1.6 Hz, 1H), 7.52-7.37 (m, 3H), 7.29 (dd, J=4.7, 7.8 Hz,1H), 3.96 (s, 2H), 3.85 (s, 3H). [M+H]=318.09.

Example 65.3-(3-Chlorophenyl)-2-methoxy-5-(1,3-thiazol-5-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.07-8.15 (m, 1H), 7.75 (s,1H), 7.71 (d, J=2.35 Hz, 1H), 7.56-7.62 (m, 1H), 7.37-7.52 (m, 3H), 4.21(s, 2H), 3.86 (s, 3H). [M+H]=318.15.

Example 66.3-(3-Chlorophenyl)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]-2-methoxypyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.63 (s, 1H), 7.57 (s, 1H),7.50-7.40 (m, 3H), 4.03 (s, 2H), 3.85 (s, 3H), 2.48 (s, 3H), 2.28 (s,3H). [M+H]=345.17.

Example 67.3-(3-Chlorophenyl)-2-methoxy-5-[(6-methoxy-5-methylpyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.3 Hz,1H), 7.94 (d, J=2.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.59-7.52 (m, 1H),7.51-7.36 (m, 3H), 3.87-3.84 (m, 6H), 3.82 (s, 2H), 3.81 (s, 3H).[M+H]=356.09.

Example 68.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-5-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.94(d, J=2.3 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.53-7.45(m, 3H), 4.29 (s, 2H). [M+H]=354.12.

Example 69.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,3-thiazol-5-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J=2.0 Hz, 1H), 7.88-7.83 (m, 1H),7.68 (s, 1H), 7.62-7.57 (m, 1H), 7.55-7.45 (m, 3H), 4.11 (s, 2H), 2.51(s, 3H), 2.29 (s, 3H). [M+H]=381.15.

Example 70.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.0 Hz,1H), 8.26 (d, J=2.0 Hz, 1H), 8.10 (s, 2H), 7.98 (d, J=2.3 Hz, 1H), 7.60(s, 1H), 7.55 (br s, 1H), 7.52-7.43 (m, 4H), 4.09 (s, 2H). [M+H]=391.05.

Example 71.(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine

Step 1. tert-Butyl((5-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)pyridin-3-yl)methyl)carbamate.The title compound was prepared in a manner analogous to Example 1, withthe appropriate starting material substitutions.

Step 2.(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-3-yl)methanamine.Purified compound from Step 1, was treated with a solution of 20% TFA inDCM and stirred at room temperature for 4 h. The solvent was removedunder reduced pressure and the residue partitioned between EtOAc andsat. aq. NaHCO₃. The organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61-8.47 (m, 1H), 8.31 (m,2H), 8.22 (br s, 1H), 7.97-7.80 (m, 2H), 7.72-7.57 (m, 2H), 7.50 (br s,2H), 4.12-4.03 (m, 2H), 4.00 (s, 2H), 3.15 (d, J=4.7 Hz, 2H).[M+H]=377.25.

Example 72.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(6-methylpyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.91(d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.89-7.83 (m, 1H), 7.69-7.65 (m, 1H),7.67 (s, 1H), 7.61-7.54 (m, 3H), 3.97 (s, 2H), 2.39 (s, 3H).[M+H]=361.06.

Example 73.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(2-methyl-1,3-thiazol-5-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.94-7.84 (m, 1H), 7.69 (s,1H), 7.59 (s, 1H), 7.53-7.42 (m, 4H), 4.19 (s, 2H), 2.55 (s, 3H).[M+H]=368.02.

Example 74.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,3-thiazol-2-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.01 (s, 1H), 7.74-7.64 (m,1H), 7.63-7.56 (m, 2H), 7.55-7.41 (m, 4H), 4.43 (s, 2H). [M+H]=354.05.

Example 75.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methylpyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 7.72(d, J=2.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.53-7.34 (m, 3H), 4.02 (s, 2H),3.80 (s, 3H), 3.85 (s, 3H). [M+H]=327.15.

Example 76.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methoxypyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 7.72(d, J=2.3 Hz, 1H), 7.63-7.56 (m, 1H), 7.53-7.34 (m, 3H), 4.02 (s, 2H),3.80 (s, 3H), 3.85 (s, 3H). [M+H]=342.15.

Example 77.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(propan-2-yl)pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.70(d, J=2.3 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 7.35 (brs, 1H), 4.03-3.89 (m, 1H), 3.85 (s, 3H), 3.75 (s, 2H), 1.11 (d, J=6.3Hz, 6H). [M+H]=370.05.

Example 78.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine

¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.77 (s, 2H), 8.16 (d, J=2.3Hz, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.65-7.36 (m, 4H), 3.98 (s, 2H), 3.30(s, 3H). [M+H]=313.01.

Example 79.3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.3 Hz,1H), 7.57 (s, 1H), 7.52-7.38 (m, 4H), 7.28 (s, 1H), 3.84 (s, 3H), 3.75(s, 2H), 3.65 (s, 3H). [M+H]=315.02.

Example 80.3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-4-ylmethyl)pyridine

Step 1. tert-Butyl4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-1-carboxylate.The title compound was prepared in a manner analogous to Example 1, withthe appropriate starting material substitutions.

Step 2. Purified compound from step 1, was treated with a solution of20% TFA in DCM and stirred at rt for 4 h. The solvent was removed underreduced pressure and the residue partitioned between EtOAc and sat.NaHCO₃. The organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated under reduced pressure to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=2.0 Hz, 1H), 7.62 (d,J=2.0 Hz, 1H), 7.58-7.54 (m, 3H), 7.50-7.36 (m, 4H), 3.84 (s, 3H), 3.72(s, 2H). [M+H]=301.02.

Example 81.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-methylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.84(br s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36(m, 3H), 3.83 (s 3H), 3.80-3.75 (m, 3H), 3.73 (s, 2H). [M+H]=342.05.

Example 82.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.84(br s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36(m, 3H), 3.80 (s, 3H), 3.78 (s, 2H), 2.68-2.56 (m, 1H), 0.71-0.61 (m,2H), 0.53-0.38 (m, 2H). [M+H]=368.02.

Example 83.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 8.16 (d, J=2.0 Hz, 1H), 7.72(d, J=2.0 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.50-7.36 (m, 3H), 3.86 (s3H), 3.73 (s, 2H), 3.01 (s, 6H). [M+H]=355.18.

Example 84.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 2H), 8.16 (d, J=2.0 Hz, 1H), 7.84(br s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.50-7.36(m, 3H), 4.10-4.01 (m, 2H), 3.86 (s 3H), 3.73 (s, 2H). [M+H]=409.14.

Example 85. Methyl4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate

[M+H]=369.16

Example 86.4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile

[M+H]=336.6.

Example 87.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.98(t, J=3.72 Hz, 1H), 7.69-7.52 (m, 1H), 7.41 (d, J=5.09 Hz, 2H), 4.03 (s,3H), 3.98 (s, 2H). [M+H]=328.21.

Example 88.3-(3-Chlorophenyl)-5-[(4-fluorophenyl)methyl]-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.51 (t, J=2.5 Hz,2H), 7.42-7.21 (m, 5H), 7.01 (t, J=8.8 Hz, 2H), 3.95 (s, 2H), 3.92 (s,3H). [M+H]=328.26.

Example 89.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 2H), 8.01 (d, J=2.3 Hz, 1H),7.70-7.63 (m, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.38-7.28 (m, 3H), 3.78(s, 2H). [M+H]=363.30.

Example 90.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide

Step 1. Methyl5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate. Thetitle compound was prepared in a manner analogous to Example 1 from(6-(methoxycarbonyl)pyridin-3-yl)boronic acid and Intermediate 3.[M+H]=370.10.

Step 2.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide.A solution of5-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)picolinate (fromStep 1) and ammonia (7N in methanol) was heated at 60° C. for 8 h, thenconcentrated under reduced pressure. Trituration with diethyl etherobtained the title compound (12 mg, 70%) as a yellow solid. ¹H NMR (400MHz, CD₃OD) δ 8.66 (br s, 1H), 8.14 (s, 1H), 8.07 (d, J=7.83 Hz, 1H),8.02 (s, 1H), 7.69-7.60 (m, 1H), 7.59-7.50 (m, 1H), 7.41 (d, J=4.70 Hz,2H), 4.27 (s, 2H), 4.00-4.09 (m, 3H). [M+H]=355.10.

Example 91.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-cyclopropylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.25 (br s, 2H), 8.11 (br s, 1H), 7.75 (br s,1H), 7.48-7.68 (m, 2H), 7.35-7.46 (m, 3H), 3.90 (br s, 2H), 2.63 (br s,1H), 0.76 (d, J=6.26 Hz, 2H), 0.51 (br s, 2H). [M+H]=403.12.

Example 92.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methoxypyrimidine

¹H NMR (400 MHz, CD₃OD) δ 8.49 (br s, 2H), 8.13 (br s, 1H), 7.78 (d,J=2.74 Hz, 1H), 7.63-7.49 (m, 2H), 7.47-7.31 (m, 3H), 4.07-3.81 (m, 5H).[M+H]=376.20.

Example 93.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.20 (br s, 2H), 8.10 (br s, 1H), 7.74 (br s,2H), 7.68-7.49 (m, 1H), 7.46-7.27 (m, 3H), 3.87 (br s, 2H), 2.89 (br s,3H). [M+H]=377.10.

Example 94.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrnmidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.27 (br s, 2H), 8.10 (br s, 1H), 7.80-7.68(m, 1H), 7.61-7.49 (m, 1H), 7.47-7.31 (m, 4H), 4.19-4.02 (m, 2H), 3.90(br s, 2H). [M+H]=445.10.

Example 95.3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.09 (s, 1H), 8.43 (s, 1H), 8.05(s, 1H), 8.02-7.95 (m, 1H), 7.47-7.38 (m, 2H), 4.20-3.90 (m, 5H).[M+H]=302.10.

Example 96.3-(3-Chlorophenyl)-2-methoxy-5-(1,2-oxazol-4-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H),7.60-7.53 (m, 2H), 7.46-7.27 (m, 3H), 3.93 (s, 3H), 3.85 (s, 2H).[M+H]=301.10.

Example 97.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1,2-oxazol-4-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.36 (s, 1H), 8.12 (d, J=1.96Hz, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.48-7.31 (m, 3H),3.91 (s, 2H). [M+H]=337.10.

Example 98.3-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.07-7.88 (m, 2H), 7.46-7.30 (m, 3H), 4.03 (s,3H), 3.89 (br s, 2H), 2.40 (br s, 3H), 2.21 (s, 3H). [M+H]=330.79.

Example 99.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.01 (br s, 1H), 7.64 (br s, 1H), 7.58 (br s,1H), 7.53 (br s, 1H), 7.47-7.31 (m, 3H), 3.81 (br s, 2H), 2.36 (br s,3H), 2.12 (br s, 3H). [M+H]=365.20.

Example 100. Methyl2-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetate

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.35 Hz, 1H), 8.02 (d, J=2.35 Hz,1H), 7.76 (s, 1H), 7.71-7.66 (m, 1H), 7.56-7.59 (m, 1H), 7.55 (s, 1H),7.57-7.46 (m, 1H), 7.45-7.36 (m, 4H), 4.01 (s, 2H), 3.67 (s, 3H), 3.61(s, 2H). [M+H]=418.29.

Example 101. Ethyl1-(4-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.35 Hz, 1H), 7.76 (s, 1H), 7.68(d, J=2.35 Hz, 1H), 7.59-7.52 (m, 1H), 7.52-7.47 (m, 2H), 7.45-7.36 (m,4H), 7.31-7.27 (m, 1H), 4.10-4.05 (m, 4H), 4.03 (m, 1H), 4.00 (s, 2H),1.55-1.49 (m, 2H), 1.14-1.19 (m, 3H). [M+H]=445.10.

Example 102.3-(3-Chlorophenyl)-5-{[6-(cyclopropylmethoxy)pyridin-3-yl]methyl}-2-(difluoromethoxy)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.08-8.05 (m, 1H), 8.01-7.90 (m, 1H), 7.71 (d,J=2.35 Hz, 1H), 7.58 (s, 1H), 7.50-7.45 (m, 1H), 7.43-7.36 (m, 4H),6.75-6.73 (m, 1H), 4.05 (d, J=7.04 Hz, 2H), 3.96 (s, 2H), 1.32-1.17 (m,1H), 0.52-0.63 (m, 2H), 0.25-0.36 (m, 2H). [M+H]=417.33.

Example 103.5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.73 (d, J=1.6 Hz, 1H), 8.13 (s, 1H),8.01-7.90 (m, 2H), 7.86 (t, J=1.8 Hz, 1H), 7.80 (dd, J=0.8, 7.8 Hz, 1H),7.46 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.0, 8.2 Hz, 1H), 7.05-6.59 (m, 1H),4.48 (q, J=7.3 Hz, 2H), 4.27 (s, 2H), 1.43 (t, J=7.0 Hz, 3H).[M+H]=383.26.

Example 104.5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 2H), 8.13 (s, 1H), 7.95 (qd, J=0.9,7.9 Hz, 1H), 7.89-7.85 (m, 1H), 7.47 (t, J=8.2 Hz, 1H), 7.20 (dd, J=3.3,8.0 Hz, 1H), 7.05-6.62 (m, 1H), 4.49 (q, J=7.2 Hz, 2H), 4.07 (s, 2H),1.43 (t, J=7.0 Hz, 3H). [M+H]=374.14.

Example 105.5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.17 (m, 2H), 8.15 (s, 1H), 8.05-8.02(m, 1H), 7.99 (ddd, J=1.6, 3.6, 5.4 Hz, 1H), 7.52-7.47 (m, 2H), 6.44 (s,2H), 4.41 (q, J=7.0 Hz, 2H), 3.90 (s, 2H), 1.35 (t, J=7.0 Hz, 3H).[M+H]=342.15.

Example 106.5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.23-8.14 (m, 3H), 7.88 (d, J=8.2 Hz, 1H),7.77 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.29-7.21 (m, 1H), 7.09-5.70 (m,3H), 3.95 (s, 3H), 3.90 (s, 2H). [M+H]=360.21.

Example 107.5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 2H), 8.19 (s, 1H), 7.90 (td, J=1.4,7.8 Hz, 1H), 7.79 (t, J=2.2 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.19 (dd,J=2.3, 8.2 Hz, 1H), 7.03-6.62 (m, 1H), 4.28 (s, 2H), 4.04 (s, 3H).M+H]=370.19.

Example 108.5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 2H), 8.17 (s, 1H), 8.06-8.02 (m, 1H),7.97 (ddd, J=1.6, 3.7, 5.3 Hz, 1H), 7.43-7.38 (m, 2H), 4.49 (q, J=7.0Hz, 2H), 4.27 (s, 2H), 1.43 (t, J=7.0 Hz, 3H). [M+H]=352.26.

Example 109.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine

Step 1.((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II)bromide. To a suspension of zinc (42.77 mg, 0.65 mmol) in THF (1 mL) wasadded 1,2-dibromoethane (2.48 μl, 0.03 mmol). The resulting mixture washeated at 70° C. for 10 minutes before being cooled to room temperature.Once cooled, trimethylsilylchloride (2.92 μL, 0.02 mmol) was added andthe solution was stirred at room temperature for an additional 30 min.To the activated zinc solution was added5-(bromomethyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine(Intermediate 12, 200 mg, 0.57 mmol) and the resulting mixture washeated at 70° C. for 8 h. The reaction mixture was cooled to roomtemperature and decanted from the solids to afford a ˜0.5 M solution ofthe title compound.

Step 2.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(pyridin-2-ylmethyl)pyridine.To a solution of 2-bromopyridine (29.89 μL, 0.31 mmol) and Pd(PPh₃)₄(9.88 mg, 0.01 mmol) in THF (3.00 mL) was added((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)zinc(II)bromide (500.00 μL, 0.57 mol/L, 0.29 mmol, from step 1). The resultingsolution was heated at 70° C. for 5 h. The solvent was removed, and thecrude material was purified on the Shimadzu HPLC using the 5-95%gradient with TFA to obtain the title compound TFA salt as an oil (21mg, 16%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.72-8.78 (m, 1H), 8.46 (dt,J=1.57, 8.02 Hz, 1H), 8.23 (d, J=2.35 Hz, 1H), 7.84-7.93 (m, 3H),7.39-7.83 (m, 5H), 4.50 (s, 2H). [M+H]=347.08.

Examples 110-111 were prepared in a manner analogous to Example 109,with the appropriate starting materials and reagent substitutions.

Example 110.2-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.65 (d, J=1.57 Hz, 1H), 8.55 (dd, J=1.57,2.74 Hz, 1H), 8.47 (d, J=2.74 Hz, 1H), 8.18 (d, J=2.35 Hz, 1H), 7.86 (d,J=2.35 Hz, 1H), 7.79-7.36 (m, 5H), 4.25 (s, 2H). [M+H]=348.06.

Example 111.6-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridazin-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18 (d, J=2.35 Hz, 1H), 7.84 (d, J=2.35 Hz,1H), 7.79 (d, J=2.35 Hz, 1H), 7.39-7.78 (m, 6H), 4.19 (s, 2H).[M+H]=363.16.

Example 112.3-(3-Chlorophenyl)-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

To a solution of3-(chloromethyl)-5-(3-chlorophenyl)-6-methoxy-2-methylpyridine(Intermediate 8, 87 mg, 0.31 mmol), in acetone (12 mL), was added1H-1,2,4-triazole (32 mg, 0.46 mmol), and Cs₂CO₃ (150 mg, 0.63 mmol).The reaction mixture stirred at room temperature for 2 h, then filteredand concentrated under reduced pressure. Purification (FCC, SiO₂,0-100%, EtOAc/hexanes) afforded the title compound (82.4 mg, 84%). ¹HNMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.52 (s, 1H),7.45-7.37 (m, 2H), 7.37-7.29 (m, 2H), 5.34 (s, 2H), 3.98 (s, 3H), 2.52(s, 3H). [M+H]=315.22.

Examples 113, 115, 117, 123, 125-126 were prepared in a manner analogousto Example 13, with the appropriate starting materials and reagentsubstitutions.

Example 113.4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.02-8.08 (m, 2H), 7.98 (td, J=4.30, 1.57 Hz,1H), 7.81 (d, J=8.22 Hz, 2H), 7.47-7.37 (m, 4H), 4.21 (s, 2H), 4.02 (s,3H). [M+H]=354.20.

Example 114.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90,with the appropriate starting material substitutions. ¹H NMR (400 MHz,CD₃OD) δ 8.49 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.95 (d, J=8.2Hz, 1H), 7.75 (dd, J=2.0, 8.2 Hz, 1H), 7.71-7.27 (m, 6H), 4.07 (s, 2H).[M+H]=390.16.

Example 115.5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.14 (d, J=2.35 Hz, 1H), 7.81(d, J=2.35 Hz, 1H), 7.38-7.30 (m, 1H), 7.59 (s, 1H), 7.10-7.03 (m, 2H)6.95 (dd, J=8.22, 1.57 Hz, 1H) 3.81 (s, 3H) 4.17 (s, 2H). [M+H]=387.32.

Example 116.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90,with the appropriate starting material substitutions. ¹H NMR (400 MHz,CD₃OD) δ 8.56 (d, J=1.6 Hz, 1H), 8.09-8.00 (m, 2H), 7.82 (dd, J=2.0, 8.2Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.53 (s, 1H), 7.45-7.30 (m, 3H), 4.09(s, 2H), 3.93 (s, 3H). [M+H]=354.20.

Example 117.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 2H), 8.18 (d, J=2.3 Hz, 1H), 7.84 (d,J=2.3 Hz, 1H), 7.80-7.37 (m, 5H), 4.18 (s, 2H). [M+H]=391.16.

Example 118.5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.65 (d,J=2.3 Hz, 1H), 7.45-7.26 (m, 3H), 7.10-7.02 (m, 1H), 4.12 (s, 2H), 3.94(s, 3H). [M+H]=339.18.

Example 119.5-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H), 7.46-7.35 (m, 3H), 7.17-7.08 (m, 1H), 7.03-6.61 (m, 1H),4.40 (q, J=7.0 Hz, 2H), 4.12 (s, 2H), 1.35 (t, J=7.0 Hz, 3H).[M+H]=401.27.

Example 120.5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.33-8.27 (m, 2H), 8.12 (br s,1H), 7.95 (d, J=2.3 Hz, 1H), 7.93-7.55 (m, 2H), 7.50 (dd, J=1.6, 5.5 Hz,1H), 7.32-7.29 (m, 1H), 4.09 (s, 2H), 3.91 (s, 3H). [M+H]=388.24.

Example 121.5-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H), 7.46-7.35 (m, 2H), 7.32 (t, J=1.8 Hz, 1H), 7.14-7.10 (m,1H), 6.83 (t, J=1.0 Hz, 1H), 4.13 (s, 2H), 3.95 (s, 3H). [M+H]=387.25.

Example 122.5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 2H), 8.23-8.15 (m, 2H), 7.79 (s, 1H),7.75-7.36 (m, 2H), 7.22-7.20 (m, 1H), 4.44 (q, J=7.0 Hz, 2H), 4.13 (s,2H), 1.37 (t, J=7.0 Hz, 3H). [M+H]=402.26.

Example 123.5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 2H), 8.20 (s, 1H), 8.02 (s, 1H),7.99-7.91 (m, 1H), 7.41 (d, J=5.09 Hz, 2H), 4.28 (s, 2H), 4.04 (s, 3H).[M+H]=356.20.

Example 124.5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide

The title compound was prepared in a manner analogous to Example 90,with the appropriate starting material substitutions. ¹H NMR (400 MHz,CD₃OD) δ 8.66-8.63 (m, 1H), 8.11 (s, 1H), 8.04 (dd, J=0.8, 7.8 Hz, 1H),7.98-7.85 (m, 3H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.0, 8.2 Hz, 1H),7.04-6.61 (m, 1H), 4.48 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.43 (t, J=7.0Hz, 3H). [M+H]=401.25.

Example 125.5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.29 (s, 1H), 8.12 (br s, 1H),7.88-7.82 (m, 1H), 7.74 (t, J=2.0 Hz, 1H), 7.71 (br s, 1H), 7.52 (t,J=8.0 Hz, 1H), 7.45-7.03 (m, 2H), 4.26 (s, 2H), 3.96 (s, 3H).[M+H]=388.15.

Example 126.5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.27 (s, 1H), 8.13 (br s, 1H),8.04-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.71 (br s, 1H), 7.52-7.45 (m,2H), 4.48-4.37 (m, 2H), 4.25 (s, 2H), 1.40-1.28 (m, 3H). [M+H]=370.05.

Example 127. Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate

To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyrazine(Intermediate 3, 200.00 mg, 0.64 mmol), in acetone (3.19 mL), was addedmethyl 1H-1,2,4-triazole-3-carboxylate (121.60 mg, 0.96 mmol) and K₂CO₃(264.44 mg, 1.91 mmol). The reaction was stirred at rt for 2 h. TheLC/MS showed two peaks with [M+H] values consistent with the two majorregioproducts. The mixture was diluted with DCM (5 mL), dried (Na₂SO₄)and concentrated under reduced pressure. Purification (FCC, SiO₂,20-100% EtOAc/hexanes) afforded the title compound (100 mg, 44%). ¹H NMR(400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.26 (s, 1H), 8.01 (td, J=1.1, 2.1 Hz,1H), 7.99-7.90 (m, 1H), 7.45-7.36 (m, 2H), 5.64 (s, 2H), 4.07 (s, 3H),3.92 (s, 3H). [M+H]=360.24.

Examples 128-149, 151-197 were prepared in a manner analogous to Example4 or Example 127 with the appropriate starting materials and reagentsubstitutions.

Example 128.3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-(difluoromethoxy)pyridine

¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.71-7.63 (m, 1H), 7.50 (d,J=19.17 Hz, 1H), 7.39 (s, 2H), 7.26 (s, 2H), 5.26 (s, 2H), 3.70 (s, 1H),2.04 (s, 1H), 1.55 (s, 1H), 0.95 (d, J=6.65 Hz, 3H). [M+H]=377.22.

Example 129.3-(3-Fluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.00 (s,1H), 7.75 (d, J=2.3 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.26 (m, 2H),7.12-7.05 (m, 1H), 5.44 (s, 2H), 3.95 (s, 3H). [M+H]=285.26.

Example 130.3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.20 (s, 1H), 8.01 (s, 2H),7.98-7.92 (m, 1H), 7.44-7.39 (m, 2H), 5.58 (s, 2H), 4.06 (s, 3H).[M+H]=302.31.

Example 131.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 8.02 (s,1H), 7.92 (d, J=2.3 Hz, 1H), 7.83-7.61 (m, 1H), 7.56 (s, 1H), 7.50-7.39(m, 3H), 5.51 (s, 2H). [M+H]=337.15.

Example 132.3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 2H), 8.18 (d, J=6.65 Hz, 2H),7.90-8.05 (m, 4H), 7.85 (s, 2H), 7.37-7.47 (m, 4H), 5.50 (d, J=10.17 Hz,4H), 4.07 (s, 6H), 2.27-2.69 (m, 6H). [M+H]=316.22.

Example 133.3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.16 (s, 2H), 8.01 (d, J=1.2 Hz,4H), 7.78 (s, 1H), 7.44-7.39 (m, 4H), 5.62 (s, 2H), 5.45 (s, 2H), 4.06(m, 6H), 2.43-2.33 (m, 1H), 2.04-1.94 (m, 1H), 1.20-0.84 (m, 8H).[M+H]=342.33.

Example 134.3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=2.3 Hz, 1H), 8.12 (s, 1H), 7.98 (s,1H), 7.55 (d, J=2.3 Hz, 1H), 7.51 (d, J=0.8 Hz, 1H), 7.43-7.32 (m, 3H),5.33 (s, 2H), 3.98 (s, 3H). [M+H]=301.19.

Example 135.3-(3-Chlorophenyl)-2-(propan-2-yloxy)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.63-8.57 (m, 1H), 8.16 (d, J=2.3 Hz, 1H),8.00 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.56 (s, 1H), 7.49-7.31 (m, 3H),5.44-5.40 (m, 3H), 1.31 (d, J=6.3 Hz, 6H). [M+H]=329.26.

Example 136.3-[2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridin-3-yl]benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.99(m, 2H), 7.91-7.83 (m, 3H), 7.69-7.62 (m, 1H), 5.43 (s, 2H), 3.90 (s,3H). [M+H]=292.26.

Example 137.2-Methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.00 (s,1H), 7.77 (d, J=2.3 Hz, 1H), 7.54-7.45 (m, 3H), 7.27 (d, J=6.3 Hz, 1H),5.45 (s, 2H), 3.96 (s, 3H). [M+H]=351.29.

Example 138.3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-4H-1,2,4-triazol-4-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.66 (d,J=2.3 Hz, 1H), 7.55 (s, 1H), 7.47-7.33 (m, 3H), 5.27 (s, 2H), 3.96 (s,3H), 2.45 (s, 3H). [M+H]=315.10.

Example 139.3-(3,5-Difluorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.00 (s,1H), 7.80 (d, J=2.3 Hz, 1H), 7.18 (dd, J=2.0, 8.6 Hz, 2H), 7.00-6.89 (m,1H), 5.44 (s, 2H), 3.97 (s, 3H). [M+H]=303.09.

Example 140. Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 8.31-8.23 (m, 1H), 8.00 (s, 1H), 7.70-7.63 (m,1H), 7.52-7.45 (m, 1H), 7.41-7.29 (m, 3H), 5.79 (s, 2H), 4.05-3.92 (m,6H). [M+H]=359.33.

Example 141. Methyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 8.21-8.18 (m, 1H), 8.18-8.15 (m, 1H), 7.56 (s,1H), 7.50 (d, J=1.2 Hz, 1H), 7.38-7.33 (m, 3H), 5.41 (s, 2H), 3.99 (m,6H). [M+H]=359.35.

Example 142.3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.3 Hz,1H), 7.99 (s, 1H), 7.82 (s, 1H), 7.56-7.49 (m, 4H), 7.42-7.32 (m, 6H),5.26 (m, 4H), 3.98 (m, 6H), 2.49 (s, 3H), 2.40 (s, 3H). [M+H]=315.22.

Example 143.3-[3-(Difluoromethyl)phenyl]-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.95(s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.73-7.62 (m, 2H), 7.62-7.51 (m, 2H),7.23-6.90 (m, 1H), 5.42 (s, 2H), 3.86 (s, 3H). [M+H]=317.21.

Example 144.3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.0 Hz,1H), 7.61 (d, J=2.3 Hz, 1H), 7.52 (d, J=1.2 Hz, 2H), 7.45-7.31 (m, 3H),6.33 (s, 1H), 5.35 (s, 2H), 3.94 (s, 3H). [M+H]=300.15.

Example 145.3-(3-Chlorophenyl)-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.56 (s, 1H), 7.49-7.31 (m, 3H), 5.50 (s, 2H), 3.96 (s,3H). [M+H]=369.17.

Example 146.3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 2H), 8.18-8.12 (m, 2H), 7.81-7.32 (m,10H), 5.50 (s, 2H), 5.32 (s, 2H), 3.97-3.93 (m, 6H), 2.29-2.19 (m, 1H),2.04-1.98 (m, 1H), 1.17-0.83 (m, 8H). [M+H]=341.23.

Example 147.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.58-7.32 (m, 14H), 5.43 (d, J=13.3 Hz, 4H),2.58-2.29 (m, 6H). [M+H]=351.17.

Example 148.3-(3-Chlorophenyl)-2-methoxy-5-{[4-(trifluoromethyl)-1H-imidazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.48 (br s, 1H), 8.24 (br s, 1H), 8.02 (m,2H), 7.88-7.62 (m, 4H), 5.58 (m, 2H), 4.25 (s, 3H). [M+H]=368.10

Example 149.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine

Step 1. 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol. Asolution of 5-(3-chlorophenyl)-6-(difluoromethoxy)nicotinaldehyde(Example 36 product from Step 2., 287 mg, 1.0 mmol) in DCM (5 mL) wascooled to 0° C. and methylmagnesium bromide (1.5 mL of a 1M solution intoluene, 1.5 mmol) was added dropwise. The mixture was warmed to roomtemperature and stirred for 30 minutes. A saturated aqueous solution ofammonium chloride was added and the mixture was extracted into DCM. Thecombined extracts were dried (Na₂SO₄), filtered and solvent removedunder reduced pressure. Purification (FCC, SiO₂, 0-60%, EtOAc/hexanes)gave 1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231mg, 70%). [M+H]=300.1.

Step 2. A solution of1-(5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)ethanol (231 mg,0.76 mmol) and DIPEA (196 mg, 1.52 mmol) in THF (5 mL) was cooled to 0°C. and methansulfonyl chloride (108 mg, 0.92 mmol) was added. Themixture was warmed to room temperature and stirred for 1 hour. The LCMSconfirmed the disappearance of the starting material. All solvents wereremoved in vacuo and the crude material purified (FCC, SiO₂, 0-60%,EtOAc/hexanes) to give the desired intermediate mesylate (205 mg, 70%)which was not characterized, and used directly in the next step.

Step 3.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[1-(1H-1,2,4-triazol-1-yl)ethyl]pyridine.The mesylate from the previous step (90 mg, 0.23 mmol) was reacted in amanner analogous to Example 127, with the appropriated starting materialsubstitutions. Purification (FCC, SiO₂, 50-100%, EtOAc/hexanes) gave thetitle compound (56 mg, 69%). ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H),8.24 (d, J=2.3 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.82-7.59(m, 1H), 7.54 (s, 1H), 7.48-7.40 (m, 3H), 5.86 (d, J=7.0 Hz, 1H), 1.96(d, J=7.0 Hz, 3H). [M+H]=351.19.

Example 150.3-(3-Fluorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 8.11 (d,J=2.3 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.67 (d, J=2.3 Hz,1H), 7.45-7.25 (m, 6H), 7.11-7.04 (m, 2H), 5.38 (s, 2H), 5.34 (s, 2H),3.95 (m, 6H), 2.51 (s, 3H), 2.32 (s, 3H). [M+H]=299.16.

Example 151.3-(3-Chlorophenyl)-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.58 (s, 1H), 7.49-7.32 (m, 3H), 5.49 (s, 2H), 4.42 (d,J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H). [M+H]=383.18.

Example 152.3-(3-Chlorophenyl)-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.14-8.11 (m, 2H), 7.71 (d, J=2.3 Hz, 1H),7.55 (s, 1H), 7.46-7.33 (m, 3H), 5.59 (s, 2H), 4.41 (d, J=7.0 Hz, 2H),1.34 (t, J=7.2 Hz, 3H). [M+H]=383.18.

Example 153.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(4-methyl-1H-imidazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.3 Hz,1H), 7.67-7.43 (m, 6H), 6.93 (s, 1H), 5.14 (s, 2H), 2.02 (s, 3H).[M+H]=350.18.

Example 154.3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyridine

As a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.19-8.09 (m, 2H), 7.74-7.65 (m,3H), 7.47-7.29 (m, 6H), 7.17-7.10 (m, 2H), 7.04-6.64 (m, 2H), 5.40-5.37(m, 2H), 5.34 (s, 2H), 3.94 (m, 6H), 2.51 (s, 3H), 2.32 (s, 3H).[M+H]=347.23.

Example 155.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 7.97 (d,J=2.3 Hz, 1H), 7.82-7.40 (m, 5H), 5.58 (s, 2H). [M+H]=362.01.

Example 156.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.91 (d,J=2.3 Hz, 1H), 7.80-7.40 (m, 5H), 5.48 (s, 2H), 4.46 (s, 2H), 3.36 (s,3H). [M+H]=381.17.

Example 157.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J=2.3 Hz, 1H), 7.94 (s, 1H), 7.90 (d,J=2.3 Hz, 1H), 7.80-7.40 (m, 5H), 5.51 (s, 2H), 4.71 (s, 2H), 3.37 (s,3H). [M+H]=381.17.

Example 158.3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.47-7.36 (m, 2H), 7.33 (d, J=2.0 Hz, 1H), 7.17-7.11 (m,1H), 7.03-6.64 (m, 1H), 5.50 (s, 2H), 3.96 (s, 3H). [M+H]=401.19.

Example 159.3-[3-(Difluoromethoxy)phenyl]-2-methoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=2.3 Hz, 1H), 8.12 (s, 1H), 7.72 (d,J=2.3 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.37 (s, 1H), 7.30 (s, 1H),7.16-7.11 (m, 1H), 7.03-6.65 (m, 1H), 5.60 (s, 2H), 3.95 (s, 3H).[M+H]=401.19.

Example 160.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(1H-1,2,3,4-tetrazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.73 (d,J=2.3 Hz, 1H), 7.39 (s, 5H), 5.64 (s, 2H). [M+H]=338.15.

Example 1613-(3-Chlorophenyl)-2-(difluoromethoxy)-5-(2H-1,2,3,4-tetrazol-2-ylmethyl)pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.82 (d,J=2.7 Hz, 1H), 7.73-7.34 (m, 5H), 5.85 (s, 2H). [M+H]=338.15.

Example 162.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.21 (d, J=2.38 Hz, 1H), 7.81(d, J=2.38 Hz, 1H), 7.48-7.35 (m, 3H), 7.18-7.06 (m, 1H), 7.06-6.60 (m,1H), 5.50 (s, 2H), 4.42 (q, J=7.07 Hz, 2H), 1.35 (t, J=7.09 Hz, 3H).[M+H]=415.21.

Example 163.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 2H), 7.74 (d, J=2.51 Hz, 1H),7.49-7.42 (m, 1H), 7.40-7.34 (m, 2H), 7.14 (dd, J=7.40, 1.76 Hz, 1H),7.05-6.63 (m, 1H) 5.60 (s, 2H), 4.41 (q, J=7.03 Hz, 2H), 1.35 (t, J=7.09Hz, 3H). [M+H]=415.21.

Example 164.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.76 (d,J=2.3 Hz, 1H), 7.49-7.35 (m, 3H), 7.13 (td, J=2.0, 7.8 Hz, 1H),7.04-6.63 (m, 1H), 5.41 (s, 2H), 4.47 (s, 2H), 4.41 (q, J=7.0 Hz, 2H),3.37 (s, 3H), 1.35 (t, J=7.2 Hz, 3H). [M+H]=391.28.

Example 165.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=2.3 Hz, 1H), 7.93 (s, 1H), 7.75 (d,J=2.3 Hz, 1H), 7.49-7.33 (m, 3H), 7.12 (tdd, J=1.0, 2.1, 7.7 Hz, 1H),7.04-6.60 (m, 1H), 5.44 (s, 2H), 4.70 (s, 2H), 4.40 (q, J=7.0 Hz, 2H),3.38 (s, 3H), 1.34 (t, J=7.0 Hz, 3H). [M+H]=391.25.

Example 166.5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=2.7 Hz, 1H), 7.84 (s, 1H), 7.67 (d,J=2.3 Hz, 1H), 7.49-7.30 (m, 4H), 7.15-7.10 (m, 1H), 7.03-6.64 (m, 1H),5.30 (s, 2H), 3.94 (s, 3H). [M+H]=366.16.

Example 167.1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J=2.3 Hz, 1H), 7.78 (d, J=2.3 Hz,1H), 7.70 (d, J=2.3 Hz, 1H), 7.57 (s, 1H), 7.48-7.43 (m, 1H), 7.41-7.32(m, 2H), 6.76 (d, J=2.3 Hz, 1H), 5.39 (s, 2H), 4.41 (q, J=7.0 Hz, 2H),1.34 (t, J=7.0 Hz, 3H). [M+H]=357.29.

Example 168. Ethyl1-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.20 (d, J=2.35 Hz, 1H),7.87-7.76 (m, 2H), 7.57 (s, 1H), 7.56-7.32 (m, 3H), 5.35 (s, 2H), 4.18(q, J=7.04 Hz, 2H), 3.87 (s, 3H), 1.23 (t, J=7.04 Hz, 3H). [M+H]=372.13.

Example 169.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.20 (d, J=1.96 Hz, 1H), 8.05(s, 1H), 7.81 (d, J=1.96 Hz, 1H), 7.61-7.31 (m, 4H), 5.39 (s, 2H), 3.87(s, 3H). [M+H]=328.08.

Example 170.2-Methoxy-3-(pyridin-4-yl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J=3.91 Hz, 2H), 8.67 (s, 1H), 8.35(s, 1H), 8.00 (dd, J=13.30, 7.83 Hz, 4H), 5.45 (s, 2H), 3.93 (s, 3H).[M+H]=298.15.

Example 171.N-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)acetamide

The title compound was isolated as a bi-product from Example 236. ¹H NMR(400 MHz, CD₃OD) δ 8.04 (d, J=1.57 Hz, 1H), 7.95 (s, 1H), 7.57 (d,J=1.57 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.34-7.29 (m, 3H), 5.22 (s,2H), 3.88 (s, 3H), 2.01 (s, 3H). [M+H]=357.32.

Example 172.3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=2.3 Hz, 1H), 7.84-7.77 (m, 2H),7.58 (d, J=0.8 Hz, 1H), 7.53-7.39 (m, 3H), 7.26 (s, 1H), 6.87 (s, 1H),5.17 (s, 2H), 3.93-3.78 (m, 3H). [M+H]=301.12.

Example 173.2-(Difluoromethoxy)-3-(3-fluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.73-8.62 (m, 1H), 8.32-8.20 (m, 1H),8.06-7.96 (m, 1H), 7.93-7.85 (m, 1H), 7.75-7.66 (m, 1H), 7.60-7.49 (m,1H), 7.44-7.33 (m, 1H), 7.28 (dt, J=2.3, 8.6 Hz, 1H), 5.49 (s, 1H), 5.44(s, 2H). [M+H]=321.14.

Example 174.2-(Difluoromethoxy)-3-(3-methoxyphenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.71-8.62 (m, 1H), 8.03-7.92 (m, 1H),7.91-7.87 (m, 1H), 7.73-7.68 (m, 1H), 7.55-7.51 (m, 1H), 7.43-7.37 (m,1H), 7.10-7.05 (m, 1H), 7.03-6.96 (m, 1H), 5.75 (s, 1H), 5.49 (s, 1H),5.44 (s, 1H), 3.78 (s, 3H). [M+H]=333.24.

Example 175.2-(Difluoromethoxy)-5-(1H-1,2,4-triazol-1-ylmethyl)-3-[3-(trifluoromethoxy)phenyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=9.8 Hz, 1H), 8.33-8.19 (m, 2H),8.04 (d, J=2.3 Hz, 1H), 7.98 (d, J=3.1 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H),7.70 (s, 1H), 7.67-7.39 (m, 2H), 5.50 (s, 1H), 5.44 (s, 1H).[M+H]=386.14.

Example 176.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1,2-dihydropyridin-2-one

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=1.96 Hz, 1H), 7.65 (d, J=1.96 Hz,1H), 7.52 (s, 1H), 7.42-7.32 (m, 1H), 7.36-7.29 (m, 4H), 6.61 (d, J=9.00Hz, 1H), 6.18 (t, J=6.46 Hz, 1H), 5.12 (s, 2H), 3.96 (s, 3H).[M+H]=327.17.

Example 177.5-[(4-Chloro-1H-pyrazol-1-yl)methyl]-3-(3-chlorophenyl)-2-methoxypyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H),7.60 (s, 1H), 7.55 (s, 1H), 7.50-7.40 (m, 3H), 5.24 (s, 2H), 3.86 (s,3H). [M+H]=334.07.

Example 178.3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.67 (s, 1H), 7.61-7.58 (m,1H), 7.54-7.36 (m, 4H), 7.10 (s, 1H), 5.14 (s, 2H), 3.85 (s, 3H), 3.60(s, 3H). [M+H]=314.10.

Example 179.3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.06 (s, 1H), 7.61 (s, 1H),7.57 (s, 1H), 7.52-7.38 (m, 4H), 5.54 (s, 2H), 3.85 (s, 3H).[M+H]=345.09.

Example 180.3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02(s, 1H), 8.01-7.91 (m, 1H), 7.45-7.35 (m, 2H), 5.52 (s, 2H), 4.06 (s,3H). [M+H]=346.70.

Example 181.3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02(s, 1H), 8.01-7.91 (m, 2H), 7.45-7.35 (m, 2H), 5.52 (s, 2H), 4.06 (s,3H). [M+H]=301.11.

Example 182. 3-(3-Chloroenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine

¹H NMR (400 MHz, CD₃OD) δ 9.13 (br s, 1H), 8.33 (s, 1H), 8.05-7.89 (m,2H), 7.73 (br s, 1H), 7.57 (br s, 1H), 7.48-7.35 (m, 2H), 5.60 (s, 2H),4.09 (s, 3H). [M+H]=303.11.

Example 183.3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.07-7.96 (m, 2H), 7.94 (s, 1H), 7.58 (br s,1H), 7.42 (d, J=3.91 Hz, 2H), 7.34 (s, 1H), 5.39 (s, 2H), 4.04 (s, 3H),2.09 (s, 3H). [M+H]=315.10.

Example 184.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H),7.96-7.90 (m, 2H), 7.86 (t, J=2.0 Hz, 1H), 7.85-7.82 (m, 2H), 7.46 (dt,J=1.6, 8.0 Hz, 2H), 7.21 (s, 1H), 7.19 (s, 1H), 7.04-6.64 (m, 2H), 5.50(s, 2H), 5.47 (s, 2H), 4.57-4.45 (m, 4H), 2.63 (s, 3H), 2.32 (s, 3H),1.44 (t, J=7.0 Hz, 6H). [M+H]=362.15.

Example 185.5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine

as a mixture

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.14 (s, 2H), 7.99-7.92 (m, 2H),7.89-7.85 (m, 2H), 7.78 (s, 2H), 7.48-7.44 (m, 2H), 7.21-7.18 (m, 1H),7.04-6.62 (m, 2H), 5.61 (s, 2H), 5.45 (s, 2H), 4.58-4.46 (m, 4H),2.41-2.30 (m, 1H), 1.99 (tt, J=5.2, 8.3 Hz, 1H), 1.45 (dt, J=1.6, 7.0Hz, 6H), 1.17-1.09 (m, 2H), 1.07-1.01 (m, 2H), 0.98-0.90 (m, 2H),0.90-0.85 (m, 2H). [M+H]=388.15.

Example 186.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.23 (s, 1H), 7.93-7.90 (m, 1H),7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd, J=2.0, 8.2 Hz,1H), 7.03-6.62 (m, 1H), 5.64 (s, 2H), 4.52 (q, J=7.0 Hz, 2H), 1.45 (t,J=7.0 Hz, 3H). [M+H]=416.12.

Example 187.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 8.12 (s, 1H), 7.95-7.87 (m, 1H),7.83 (t, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.2, 8.0 Hz,1H), 7.02-6.59 (m, 1H), 5.74 (s, 2H), 4.52 (q, J=7.3 Hz, 2H), 1.45 (t,J=7.0 Hz, 3H). [M+H]=416.12.

Example 188.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.96-7.91 (m, 1H),7.85 (t, J=2.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.20 (dd, J=2.0, 8.2 Hz,1H), 7.05-6.62 (m, 1H), 5.54 (s, 2H), 4.51 (q, J=7.0 Hz, 2H), 4.46 (s,3H), 4.30 (s, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=392.26.

Example 189.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.95-7.91 (m, 2H), 7.84 (d,J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd, J=2.2, 8.0 Hz, 1H),7.03-6.63 (m, 1H), 5.60 (s, 2H), 4.79 (s, 2H), 4.51 (q, J=7.0 Hz, 2H),3.38 (s, 3H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=392.15.

Example 190. Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.78 (s, 1H), 8.23 (s, 1H), 7.92 (td, J=1.4,7.8 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.19 (dd,J=2.3, 8.2 Hz, 1H), 7.03-6.63 (m, 1H), 5.63 (s, 2H), 4.51 (q, J=7.0 Hz,2H), 3.91 (s, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=406.15.

Example 191. Methyl1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.18 (s, 1H), 7.95-7.92 (m, 1H),7.87-7.85 (m, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.20 (dd, J=2.0, 8.2 Hz, 1H),7.03-6.64 (m, 1H), 5.54 (s, 2H), 4.51 (q, J=7.0 Hz, 2H), 3.35 (s, 3H),1.44 (t, J=7.0 Hz, 3H). [M+H]=406.26.

Example 192.3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 8.28 (s, 1H), 7.92 (td, J=1.4,7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd,J=2.7, 8.2 Hz, 1H), 7.03-6.62 (m, 1H), 5.67 (s, 2H), 4.53 (q, J=7.0 Hz,2H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=393.15.

Example 193.3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1H), 8.10 (s, 1H), 7.80 (td, J=1.4,7.8 Hz, 1H), 7.73 (t, J=2.3 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.18 (dd,J=2.0, 8.2 Hz, 1H), 7.02-6.61 (m, 1H), 6.01 (s, 2H), 4.51 (q, J=7.0 Hz,2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=393.21.

Example 194. Methyl1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 8.09 (s, 1H), 7.94 (td, J=1.1,2.1 Hz, 1H), 7.93-7.86 (m, 1H), 7.43-7.34 (m, 2H), 5.99 (s, 2H),4.08-4.04 (m, 3H), 3.99-3.95 (m, 3H). [M+H]=360.18.

Example 195. Methyl1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.35 (s, 1H), 7.83 (td, J=1.4,7.8 Hz, 1H), 7.72-7.68 (m, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.43-7.04 (m,2H), 5.66 (s, 2H), 3.99 (s, 3H), 3.29 (s, 3H). [M+H]=392.16.

Example 196. Methyl1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.32 (s, 1H), 7.99-7.96 (m,1H), 7.96-7.90 (m, 1H), 7.52-7.46 (m, 2H), 5.64 (s, 2H), 4.45 (q, J=7.0Hz, 2H), 3.83-3.77 (m, 3H), 1.39-1.34 (m, 3H). [M+H]=374.18.

Example 197.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide

Step 1. Methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylatewas prepared in a manner analogous to Example 127.

Step 2.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazole-4-carboxamide.To a solution of methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-imidazole-4-carboxylatein 7 N ammonia in MeOH (4 mL) was added NaCN (5 mg). Reaction mixturewas heated 24 h at 130° C. LC-MS confirms the disappearance of startingmaterial. The reaction mixture was concentrated under reduced pressure.Purification (FCC, SiO₂, 0-1%, EtOAc/MeOH) gave the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 8.18 (d, J=2.3 Hz, 1H), 8.04 (s, 1H), 7.92 (d,J=2.3 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.57-7.55 (m, 1H), 7.53-7.43(m, 3H), 5.58 (s, 2H), 3.55 (s, 1H), 3.15 (d, J=5.1 Hz, 1H).[M+H]=379.15.

Example 198.(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

To a solution of methyl1-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(Example 127, 77.00 mg, 0.21 mmol), in THF (1 mL) was added LiBH₄ (4.66mg, 0.21 mmol). The mixture was stirred at room temperature for 3 hr.The mixture was diluted with water and extracted into DCM. The combinedextracts were dried (Na₂SO₄) and concentrated under reduced pressure.Purification (FCC, SiO₂, 0-5% DCM/MeOH) afforded the title compound (50mg, 70%). ¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.21 (s, 1H), 8.02(td, J=1.1, 2.1 Hz, 1H), 8.00-7.92 (m, 1H), 7.45-7.38 (m, 2H), 5.53 (s,2H), 4.59 (s, 2H), 4.06 (s, 3H). [M+H]=332.15.

Examples 199-211 were prepared in a manner analogous to Example 198,with the appropriate starting materials and reagent substitutions.

Example 199.(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.93 (d,J=2.7 Hz, 1H), 7.82-7.38 (m, 5H), 5.46 (s, 2H), 4.59 (s, 2H).[M+H]=367.18.

Example 200.[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.76 (d,J=2.3 Hz, 1H), 7.49-7.34 (m, 3H), 7.13 (td, J=2.0, 7.8 Hz, 1H),7.02-6.65 (m, 1H), 5.39 (s, 2H), 4.59 (s, 2H), 4.40 (q, J=7.2 Hz, 2H),1.34 (t, J=7.0 Hz, 3H). [M+H]=377.25.

Example 201.[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.20 (d, J=2.7 Hz, 1H), 7.76 (d,J=2.3 Hz, 1H), 7.48-7.35 (m, 2H), 7.32 (t, J=1.8 Hz, 1H), 7.16-7.11 (m,1H), 7.03-6.65 (m, 1H), 5.49 (s, 1H), 4.59 (s, 2H), 3.95 (s, 3H).[M+H]=363.23.

Example 202.(1-((5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.18 (d, J=2.7 Hz, 1H), 7.75 (d,J=2.7 Hz, 1H), 7.60-7.56 (m, 1H), 7.49-7.45 (m, 1H), 7.42-7.33 (m, 2H),5.39 (s, 2H), 4.59 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz,3H). [M+H]=345.22.

Example 203.(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 7.89 (d,J=2.3 Hz, 1H), 7.61 (t, J=1.0 Hz, 1H), 7.38-7.31 (m, 1H), 7.10-7.03 (m,2H), 6.95 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 5.46 (s, 2H), 4.59 (s, 2H),4.07 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H). [M+H]=377.25.

Example 204.[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.28 (d, J=2.3 Hz, 1H),8.24-8.21 (m, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.76-7.37 (m, 2H), 7.20-7.17(m, 1H), 5.41 (s, 2H), 4.59 (s, 2H), 3.98 (s, 3H). [M+H]=364.22.

Example 205.[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.24(dd, J=0.8, 5.5 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.77-7.56 (m, 1H),7.44-7.41 (m, 1H), 7.23-7.20 (m, 1H), 5.41 (s, 2H), 4.59 (s, 2H), 4.45(q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). [M+H]=378.20.

Example 206.(1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.35-8.28 (m, 2H), 8.05 (d,J=2.3 Hz, 1H), 7.83-7.41 (m, 2H), 7.41-7.39 (m, 1H), 7.19-7.17 (m, 1H),5.49 (s, 2H), 4.59 (s, 2H). [M+H]=400.21.

Example 207.[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.18 (s, 1H), 7.93 (td, J=1.4,7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20 (dd,J=2.0, 8.2 Hz, 1H), 7.04-6.64 (m, 1H), 5.52 (s, 2H), 4.59 (s, 2H), 4.51(q, J=7.3 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=378.25.

Example 208.[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.93-7.89 (m, 1H),7.83 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.7, 7.8 Hz,1H), 7.05-6.62 (m, 1H), 5.65 (s, 2H), 4.91 (s, 2H), 4.50 (q, J=7.0 Hz,2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=378.15.

Example 209.(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.16 (s, 1H), 8.02-7.99 (m, 1H), 7.94 (ddd,J=1.8, 3.5, 5.3 Hz, 1H), 7.92-7.89 (m, 1H), 7.44-7.39 (m, 2H), 5.66 (s,2H), 4.90 (s, 2H), 4.06 (s, 3H). [M+H]=332.18.

Example 210.[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.88-7.83 (m,1H), 7.76-7.71 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45-7.06 (m, 2H), 5.50(s, 2H), 5.16 (t, J=6.1 Hz, 1H), 4.36 (d, J=6.3 Hz, 2H), 3.98 (s, 3H).[M+H]=364.14.

Example 211.(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.24 (s, 1H), 8.02-7.99 (m,1H), 7.99-7.93 (m, 1H), 7.54-7.48 (m, 2H), 5.49 (s, 2H), 5.16 (t, J=6.1Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 4.36 (d, J=5.9 Hz, 2H), 1.36 (t, J=7.0Hz, 3H). [M+H]=346.25.

Example 212.3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

Step 1.3-(3-Chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine.The title compound was prepared in a manner analogous to Example 127with the appropriate starting material substitutions.

Step 2.3-(3-Chlorophenyl)-2-methoxy-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine.To a solution of3-(3-chlorophenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine(135 mg, 0.39 mmol), in MeOH (3 mL) was added NaOCH₃ (63 mg, 1.17 mmol).The mixture was stirred at 60° C. for 16 h. The LC/MS showedapproximately 70% conversion. All solvents removed under reducedpressure, the residue dissolved in DCM (50 mL) and water (50 mL), thelayers shaken and separated and the aqueous layer extracted into DCM(3×50 mL). The combined extracts were dried (MgSO₄), filtered andsolvent removed under reduced pressure. Purification (FCC, SiO₂, 0-100%EtOAc/DCM) afforded the title compound (72 mg, 56%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.33 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H),7.58 (s, 1H), 7.52-7.38 (m, 3H), 5.23 (s, 2H), 3.87 (s, 3H), 3.79 (s,3H). [M+H]=331.21.

Examples 213-215 were prepared in a manner analogous to Example 212,with the appropriate starting materials and reagent substitutions.

Example 213.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.91 (d,J=2.3 Hz, 1H), 7.82-7.61 (m, 1H), 7.57 (s, 1H), 7.49-7.40 (m, 3H), 5.32(s, 2H), 3.92 (s, 3H). [M+H]=367.16.

Example 214.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(5-methoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.17 (d, J=2.0 Hz, 1H), 7.84 (d, J=2.3 Hz,1H), 7.61-7.39 (m, 6H), 5.21 (s, 2H), 4.12 (s, 3H). [M+H]=367.16.

Example 215.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-[(3-ethoxy-1H-1,2,4-triazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.28-8.21 (m, 2H), 7.91 (d, J=2.3 Hz, 1H),7.84-7.60 (m, 1H), 7.56 (s, 1H), 7.49-7.40 (m, 3H), 5.31 (s, 2H), 4.26(q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=380.18.

Example 216.1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

Step 1.3-(3-(Difluoromethoxy)phenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine.The title compound was prepared in a manner analogous to Example 127with the appropriate starting material substitutions.

Step 2.1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine.To a solution of3-(3-(difluoromethoxy)phenyl)-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine(331.00 mg, 0.88 mmol) in HOAc (6 mL), and water (2 mL) was added zinc(573.57 mg, 8.77 mmol). The mixture was stirred at 50° C. for 1 hr. Thesolvent was removed under reduced pressure to afford a white solid. Thecrude solid was dissolved in DCM (50 mL), sonicated and filtered(repeated twice). The combined DCM extracts were washed with sat. aq.NaHCO₃ and the layers separated. The organic layers were combined, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. Theresulting solid was triturated with hexanes to give the title compound(287 mg, 94%). ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=2.7 Hz, 1H), 8.13(s, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.47-7.36 (m, 2H), 7.33 (t, J=1.8 Hz,1H), 7.16-7.11 (m, 1H), 7.04-6.65 (m, 1H), 5.19 (s, 2H), 3.95 (s, 3H).[M+H]=348.22.

Examples 217-218, 223-236 were prepared in a manner analogous to Example216, with the appropriate starting materials and reagent substitutions.

Example 217.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 7.76(d, J=2.3 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.51-7.42 (m, 3H), 5.26 (s,2H), 5.11 (s, 2H), 3.88 (s, 3H). [M+H]=316.21.

Example 218.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=2.3 Hz, 1H), 8.06 (s, 1H), 7.78 (d,J=2.3 Hz, 1H), 7.73-7.50 (m, 1H), 7.47 (s, 1H), 7.41-7.30 (m, 3H), 5.15(s, 2H). [M+H]=352.17.

Example 219.1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

Step 1.3-Bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine.Title compound was prepared in a manner analogous to Intermediate 5 withthe appropriate starting materials and reagent substitutions.[M+H]=314.24/316.25.

Step 2.1-((5-Bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine. To asolution of3-bromo-2-methoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyridine (60mg, 0.191 mmol) in AcOH (3 mL), and water (1 mL) was added zinc (124 mg,1.91 mmol). The mixture was stirred at 50° C. for 1 hr. The solvent wasremoved under reduced pressure to afford a white solid. The crude solidwas dissolved in DCM (50 mL), sonicated and filtered (repeated twice).The combined DCM extracts were washed with sat. aq. NaHCO₃ and thelayers separated. The organic layers were combined, dried (Na₂SO₄),filtered and concentrated under reduced pressure. The title compound wastaken on to the next step without further purification.

Step 3.1-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine.1-((5-bromo-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine and(3-fluorophenyl) boronic (42 mg, 0.3 mmol) dissolved in mixture of water(2 mL), and ACN (4 mL) were added Pd(dppf)Cl₂ (8 mg, 0.01 mmol) followedby Na₂CO₃ (53 mg, 0.5 mmol). The mixture was irradiated under microwavesfor 15 minutes at 100° C. The reaction mixture was diluted with waterand extracted with DCM (3×5 mL). The combined organic phase was dried(Na₂SO₄), filtered, and concentrated under reduced pressure.Purification (FCC, SiO₂, 0-10% DCM/MeOH) afforded the title compound(49.7 mg, 89%). ¹H NMR (400 MHz, CD₃OD) δ 8.13 (br s, 1H), 7.71 (br s,1H), 7.63-7.23 (m, 4H), 7.08 (br s, 1H), 5.19 (m, 2H), 3.95 (s, 3H).[M+H]=300.27.

Examples 220-222 were prepared in a manner analogous to Example 220,with the appropriate starting material and reagent substitutions.

Example 220.1-{[6-Methoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 2H), 7.67 (d, J=2.3 Hz, 1H), 7.31(dd, J=8.2 Hz, 1H), 7.10-7.04 (m, 2H), 6.91 (dd, J=1.6, 8.2 Hz, 1H),5.18 (s, 2H), 3.94 (s, 3H), 3.82 (s, 3H). [M+H]=312.28.

Example 221.1-{[6-Methoxy-5-(3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.12 (m, 2H), 7.64-7.29 (m, 4H), 7.16 (br s,1H), 5.17 (br s, 2H), 3.94 (s, 3H), 2.37 (s, 3H). [M+H]=296.29.

Example 222.3-{5-[(3-Amino-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.19 (br s, 1H), 8.13 (br s, 1H), 7.92-7.68(m, 4H), 7.61 (d, J=7.8 Hz, 1H), 5.19 (br s, 2H), 3.96 (s, 3H).[M+H]=307.26.

Example 223.1-{[5-(3-Ethoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.13-8.09 (m, 2H), 7.66 (d, J=2.3 Hz, 1H),7.31-7.25 (m, 1H), 7.07-7.03 (m, 2H), 6.91-6.87 (m, 1H), 5.17 (s, 2H),4.05 (d, J=7.0 Hz, 2H), 3.93 (s, 3H), 1.39 (t, J=7.0 Hz, 3H).[M+H]=326.26.

Example 224.1-{[5-(3-Cyclopropoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.16-8.09 (m, 2H), 7.66 (d, J=2.38 Hz, 1H),7.36-7.16 (m, 2H), 7.11-7.02 (m, 2H), 5.18 (s, 2H), 3.94 (s, 3H), 3.80(tt, J=6.01, 2.96 Hz, 1H), 0.82-0.67 (m, 4H). [M+H]=338.27.

Example 225.1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.18-8.07 (m, 2H), 7.71 (d, J=2.3 Hz, 1H),7.50-7.34 (m, 3H), 7.17-7.09 (m, 1H), 7.06-6.62 (m, 1H), 5.18 (s, 2H),4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=362.24.

Example 226.1-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.22-8.11 (m, 2H), 7.84 (d, J=2.3 Hz, 1H),7.80-7.39 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.10-7.05 (m, 2H), 6.97 (dd,J=2.5, 8.4 Hz, 1H), 5.24 (s, 2H), 3.82 (s, 3H). [M+H]=348.22.

Example 227.1-{[5-(5-Chloropyridin-3-yl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 8.78 (d, J=1.76 Hz, 1H), 8.66(d, J=2.13 Hz, 1H), 8.38 (d, J=2.26 Hz, 1H), 8.31 (t, J=2.01 Hz, 1H),8.01 (d, J=2.26 Hz, 1H), 5.38 (s, 2H), 4.02 (s, 3H). [M+H]=317.21.

Example 228.1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.25-8.19 (m, 2H), 8.13 (s, 1H), 7.84 (d,J=2.3 Hz, 1H), 7.76-7.55 (m, 1H), 7.44-7.36 (m, 1H), 7.18 (d, J=0.8 Hz,1H), 5.19 (s, 2H), 3.98 (s, 3H). [M+H]=349.25.

Example 229.1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.24 (dd, J=0.8, 5.1 Hz, 1H), 8.21 (d, J=2.3Hz, 1H), 8.14 (s, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.77-7.57 (m, 1H), 7.43(dd, J=1.6, 5.5 Hz, 1H), 7.22 (dd, J=0.8, 1.6 Hz, 1H), 5.20 (s, 2H),4.47 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). [M+H]=363.19.

Example 230.1-{[6-(Difluoromethoxy)-5-[2-(difluoromethoxy)pyridin-4-yl]pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32-8.27 (m, 2H), 8.16 (s, 1H), 7.99 (d,J=2.3 Hz, 1H), 7.84-7.38 (m, 3H), 7.19-7.16 (m, 1H), 5.27 (s, 2H).[M+H]=385.20.

Example 231.1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=2.3 Hz, 1H), 7.58 (d, J=2.3 Hz,1H), 7.46-7.30 (m, 4H), 7.14-7.09 (m, 1H), 7.02-6.64 (m, 1H), 5.64 (d,J=2.3 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 3H). [M+H]=347.37.

Example 232.1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-5-amine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.55 (d, J=2.7 Hz,1H), 7.44-7.33 (m, 2H), 7.30 (t, J=2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H),7.13-7.09 (m, 1H), 7.02-6.63 (m, 1H), 5.50 (d, J=2.3 Hz, 1H), 5.16 (s,2H), 3.92 (s, 3H). [M+H]=347.37.

Example 233.4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.05 (d, J=2.7 Hz, 1H), 7.62 (d, J=2.3 Hz,1H), 7.59-7.56 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.32 (m, 2H), 5.06 (s,2H), 4.40 (q, J=7.0 Hz, 2H), 1.38-1.30 (t, J=7.0 Hz, 3H). [M+H]=363.30.

Example 234.4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-amine

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.3 Hz, 1H), 7.60-7.55 (m, 2H),7.47-7.43 (m, 1H), 7.41-7.32 (m, 2H), 7.25 (s, 1H), 5.16 (s, 2H), 4.39(q, J=7.4 Hz, 2H), 1.34 (t, J=7.0 Hz, 4H). [M+H]=363.30.

Example 235.1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine

The title compound was prepared in a manner analogous to Example 216,two products were formed. ¹H NMR (400 MHz, CD₃OD) δ 8.14 (s, 1H), 8.07(s, 1H), 8.03 (s, 1H), 7.98 (d, J=4.30 Hz, 1H), 7.61 (s, 1H), 7.47-7.39(m, 2H), 5.49 (s, 2H), 4.06 (s, 3H). [M+H]=316.10.

Example 236.1-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine

¹H NMR (400 MHz, CD₃OD) δ 8.64-8.50 (m, 1H), 8.18 (s, 1H), 7.93 (td,J=1.4, 7.8 Hz, 1H), 7.86 (t, J=2.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20(dd, J=2.0, 8.2 Hz, 1H), 7.05-6.60 (m, 1H), 5.52 (s, 2H), 4.51 (q, J=7.3Hz, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=363.14.

Example 237.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methyl1H-1,2,4-triazol-3-amine

To a solution of1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine(Example 218, 120 mg, 0.34 mmol) in DCM (2 mL), was added formaldehyde(26 μL of 37 wt % solution, 0.35 mmol), NaBH(OAc)₃ (145 mg, 0.68 mmol)and a few drops of HOAc. The mixture was stirred at room temperature for16 h. Purification by reverse-phase PREP-HPLC gave the title compound(25 mg, 20%). ¹H NMR (400 MHz, CD₃OD) δ 8.19-8.11 (m, 1H), 7.82 (d,J=2.0 Hz, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.41-7.28 (m,3H), 5.21 (s, 2H), 2.72 (s, 3H). [M+H]=366.21.

Example 238.1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N,N-dimethyl-1H-1,2,4-triazol-3-amine

Prepared as a product of the reaction from procedure as Example 237.Purification by reverse-phase PREP-HPLC gave the title compound (41 mg,32%). ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.25 (d, J=2.0 Hz, 1H),7.93 (d, J=2.3 Hz, 1H), 7.84-7.61 (m, 1H), 7.57 (s, 1H), 7.50-7.39 (m,3H), 5.32 (s, 2H), 2.96 (s, 6H). [M+H]=380.24.

Example 239.(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanamine

To a cooled solution, −78° C., of1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbonitrile(Example 155, 345 mg, 0.95 mmol) in DCM (5 mL) was slowly added DIBAL(135.64 mg, 0.95 mmol). The mixture was stirred at −78° C. for 1 h. Thereaction was quenched with wet Na₂SO₄ and stirred at room temperaturefor 30 min. The white aluminum precipitate was filtered and the filtrateconcentrated under reduced pressure. Purification (FCC, SiO₂, 40-100%EtOAc/DCM, followed by 0-10% MeOH/DCM) afforded the title compound (37mg, 10%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.25 (d, J=2.3 Hz,1H), 7.92 (d, J=2.3 Hz, 1H), 7.81-7.40 (m, 5H), 5.45 (s, 2H), 3.85-3.82(m, 2H). [M+H]=366.20.

Example 240.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazole-3-carboxamide

To a solution of methyl1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(Example 141, 103 mg, 0.28 mmol) in MeOH (2 mL) was added ammonia inmethanol (2 mL of 7N solution, 14 mmol). The mixture was heated usingmicrowave irradiation at 130° C. for 20 min. The LC/MS showed incompleteconversion. To the reaction mixture was added more ammonia in methanol(2 mL, 14 mmol) and irradiated in a microwave at 120° C. for anadditional 20 min. The solvent was removed under reduced pressure.Purification (FCC, SiO₂, 0-5% MeOH/DCM) afforded the title compound (77mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.25 (d, J=2.3 Hz,1H), 7.85 (d, J=2.3 Hz, 1H), 7.78-7.70 (m, 1H), 7.62-7.40 (m, 5H), 5.45(s, 2H), 3.87 (s, 3H). [M+H]=354.18.

Examples 241-244 were prepared in a manner analogous to Example 90, withthe appropriate starting materials and reagent substitutions.

Example 241.4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N-(oxetan-3-yl)benzamide

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=2.3 Hz, 1H), 7.71 (d, J=8.2 Hz,2H), 7.47-7.39 (m, 2H), 7.34-7.19 (m, 5H), 5.07-4.97 (m, 1H), 4.81 (d,J=7.4 Hz, 2H), 4.60 (t, J=6.5 Hz, 2H), 3.94 (s, 2H), 3.83 (s, 3H).[M+H]=409.24.

Example 242.5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-N-methylpyridine-2-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J=1.6 Hz, 1H), 8.14 (d, J=2.0 Hz,1H), 8.01 (d, J=7.8 Hz, 1H), 7.83 (dd, J=2.0, 8.2 Hz, 1H), 7.78 (d,J=2.3 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.47-7.38 (m, 3H), 4.15 (s,2H), 2.94 (s, 3H). [M+H]=404.17.

Example 243.1-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)cyclopropane-1-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.35 Hz, 1H), 7.76 (s, 1H), 7.73(d, J=2.35 Hz, 1H), 7.58 (s, 1H), 7.53-7.49 (m, 1H), 7.46-7.30 (m, 4H),7.30-7.21 (m, 2H), 4.04 (s, 2H), 1.47 (q, J=3.65 Hz, 1H), 1.09-1.00 (m,2H) 0.90-0.80 (m, 2H). [M+H]=429.10.

Example 244.2-(4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}phenyl)acetamide

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.35 Hz, 1H), 7.76 (s, 1H), 7.67(d, J=2.35 Hz, 1H), 7.57 (s, 1H), 7.50 (m, 1H), 7.34-7.44 (m, 2H),7.17-7.28 (m, 4H), 4.01 (s, 2H), 3.47 (s, 2H). [M+H]=403.29.

Example 245.2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)propan-2-ol

To a solution of1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(Example 141, 104 mg, 0.28 mmol) in DCM (2 mL) was added methylmagnesiumbromide in diethyl ether (0.28 mL of 3M solution, 0.84 mmol). Themixture was stirred at rt for 20 min. The mixture was carefully quenchedwith wet Na₂SO₄, diluted with DCM, filtered and concentrated underreduced pressure. Purification (FCC, SiO₂, 50-100% EtOAc/hexanes)afforded the title compound (67 mg, 67%). ¹H NMR (400 MHz, CDCl₃) δ 8.15(d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.59-7.48 (m, 2H), 7.42-7.31 (m, 3H),5.28 (s, 2H), 3.98 (s, 3H), 3.70 (s, 1H), 1.62 (s, 6H). [M+H]=359.09.

Examples 246-249 were prepared in a manner analogous to Example 245,with the appropriate starting materials and reagent substitutions.

Example 246.2-(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-5-yl)propan-2-ol

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=2.0 Hz, 1H), 7.79 (s, 1H), 7.64 (d,J=2.0 Hz, 1H), 7.51 (s, 1H), 7.41-7.29 (m, 3H), 5.63 (s, 2H), 3.96 (s,3H), 2.11 (s, 1H), 1.70 (s, 6H). [M+H]=359.09.

Example 247.2-(4-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 7.99 (d, J=2.0 Hz, 1H), 7.49 (d, J=1.6 Hz,2H), 7.45-7.27 (m, 5H), 7.19 (d, J=8.2 Hz, 2H), 3.94 (s, 2H), 3.65 (s,3H), 1.50 (s, 6H). [M+H]=368.23.

Example 248.2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.04 (d, J=2.0 Hz, 1H),7.70-7.58 (m, 2H), 7.57-7.48 (m, 2H), 7.43-7.28 (m, 3H), 3.99 (s, 2H),3.92 (s, 3H), 1.51 (s, 6H). [M+H]=369.23.

Example 249.2-(5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-yl)propan-2-ol

¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.3 Hz,1H), 7.78-7.57 (m, 4H), 7.52 (d, J=1.6 Hz, 1H), 7.46-7.36 (m, 3H), 4.07(s, 2H), 1.51 (s, 6H). [M+H]=405.22.

Example 250.3-[3-(Difluoromethoxy)phenyl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine

To a solution of(1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol(Example 201, 40.0 mg, 0.11 mmol) in DCM (3 mL) was added Deoxo-Fluor®(36.64 mg, 0.17 mmol). The mixture was stirred at room temperature for 2h. The material was adsorbed on silica and purified (FCC, SiO₂, 20-100%EtOAc/hexanes) to afford the title compound (11 mg, 27%). ¹H NMR (400MHz, CD₃OD) δ 8.61 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz,1H), 7.49-7.36 (m, 2H), 7.33 (t, J=2.2 Hz, 1H), 7.16-7.11 (m, 1H),7.04-6.65 (m, 1H), 5.44 (s, 2H), 5.41-5.28 (m, 2H), 3.96 (s, 3H).[M+H]=365.21.

Examples 251-255 were prepared in a manner analogous to Example 250,with the appropriate starting materials and reagent substitutions.

Example 251.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.23-8.18 (m, 2H), 7.76 (d, J=2.3 Hz, 1H),7.48-7.36 (m, 3H), 7.17-7.11 (m, 1H), 7.03-6.65 (m, 1H), 5.64 (s, 2H),5.42 (d, J=48 Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).[M+H]=379.23.

Example 252.2-(Difluoromethoxy)-3-(3-ethoxyphenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.90 (d,J=2.3 Hz, 1H), 7.81-7.42 (m, 1H), 7.38-7.31 (m, 1H), 7.10-7.03 (m, 2H),6.96 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 5.53-5.27 (m, 4H), 4.16-4.00 (q,J=7.0 Hz, 2H), 1.47-1.35 (t, J=7.0 Hz, 3H). [M+H]=379.27.

Example 253.3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 1H), 8.29 (d, J=2.3 Hz, 1H),8.26-8.21 (m, 1H), 7.90 (d, J=2.3 Hz, 1H), 7.76-7.39 (m, 2H), 7.19 (dd,J=0.8, 1.6 Hz, 1H), 5.48-5.27 (m, 4H), 4.00 (s, 3H). [M+H]=366.23.

Example 254.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.77-8.66 (m, 1H), 8.24 (s, 1H), 8.03-7.92 (m,1H), 7.87 (d, J=10.6 Hz, 1H), 7.57-7.41 (m, 1H), 7.25 (dd, J=2.7, 8.2Hz, 1H), 7.17-6.71 (m, 1H), 5.61 (s, 2H), 5.58-5.54 (m, 1H), 5.45-5.29(m, 1H), 4.61-4.47 (m, 2H), 1.52-1.43 (m, 3H). [M+H]=380.13.

Example 255.3-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine

¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.31 (s, 1H), 8.00-7.86 (m,2H), 7.58-7.45 (m, 2H), 5.58 (s, 2H), 5.38 (s, 1H), 5.26 (s, 1H), 3.99(s, 3H). [M+H]=334.16.

Example 256.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine

Step 1. Methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate.The title compound was prepared in a manner analogous to Example 127with the appropriate starting material substitutions.

Step 2.1-((5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde.To a cooled solution, −78° C., of methyl1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(146 mg, 0.37 mmol) in DCM (5 mL) was added DIBAL (52.6 mg, 0.37 mmol)slowly. The mixture was stirred at −78° C. for 1 h. The reaction wasquenched with wet Na₂SO₄ and stirred at room temperature for 30 min. Thewhite aluminum salt precipitate obtained was filtered and (the filtrate)concentrated under reduced pressure. The crude product was purified(FCC, SiO₂, 40-100% EtOAc/DCM followed by 0-5% MeOH/DCM) to afford thetitle compound (69 mg, 51%).

Step 3.3-(3-Chlorophenyl)-2-(difluoromethoxy)-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyridine.To a solution of((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carbaldehyde(69 mg, 0.19 mmol) in DCM (5 mL) was added Deoxo-Fluor® (104.6 mg, 0.47mmol). The mixture was stirred at room temperature for 16 h. The LC/MSsuggested the presence of the title compound. The material was adsorbedon silica and purified (FCC, SiO₂, 10-100% EtOAc/hexanes) to afford thetitle compound (13 mg, 18%). ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H),8.28 (d, J=2.3 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.81-7.39 (m, 5H),6.94-6.65 (m, 1H), 5.54 (s, 2H). [M+H]=387.17.

Examples 257-258 were prepared in a manner analogous to Example 256,with the appropriate starting materials and reagent substitutions.

Example 257.3-[3-(Difluoromethoxy)phenyl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-ethoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.79 (d,J=2.3 Hz, 1H), 7.51-7.35 (m, 3H), 7.18-7.10 (m, 1H), 7.04-6.63 (m, 2H),5.47 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).[M+H]=397.24.

Example 258.3-[2-(Difluoromethoxy)pyridin-4-yl]-5-{[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyridine

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.23 (d,J=5.1 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.77-7.55 (m, 1H), 7.41-7.39 (m,1H), 7.21-7.17 (m, 1H), 6.95-6.63 (m, 1H), 5.49 (s, 2H), 3.99 (s, 3H).[M+H]=384.21.

Example 259.3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine

Step 1. 5-(Azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine. To asolution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine(Intermediate 2, 160 mg, 0.51 mmol) in DMF (5 mL) was added NaN₃ (0.05g, 0.77 mmol) and K₂CO₃ (0.14 g, 1.02 mmol). The mixture was stirred atroom temperature for 16 h. The mixture was diluted with brine andextracted into diethyl ether. All solvents were removed under reducedpressure to afford the title compound, which was used in the next stepwithout further purification.

Step 2.3-(3-Chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine.To a solution of 5-(azidomethyl)-3-(3-chlorophenyl)-2-methoxypyridine(directly used from previous reaction) and ethynyltrimethylsilane (75.1mg, 0.77 mmol) in THF (3 mL), water (1 mL), was added copper (I) iodide(19.4 mg, 0.10 mmol) and DIPEA (132 mg, 1.02 mmol). The mixture wasstirred at room temperature for 2 h. The mixture was diluted with waterand extracted in to DCM. The organic layers were combined, dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purification(FCC, SiO₂, 0-50% EtOAc/hexanes) afforded the title compound (92 mg,48%). [M+H]=373.2.

Step 3.3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,3-triazol-1-ylmethyl)pyridine. Toa solution of3-(3-chlorophenyl)-2-methoxy-5-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)pyridine(92.0 mg, 0.25 mmol) in THF (3 mL) was added TBAF (129 mg, 0.49 mmol).The mixture was stirred at room temperature for 16 h. The mixture wasdiluted with water and extracted in to DCM. The DCM extracts werecombined, dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification (FCC, SiO₂, 0-80% EtOAc/DCM) afforded the titlecompound (44 mg, 59%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (br s, 1H), 7.95(s, 1H), 7.65-7.59 (m, 2H), 7.42 (br s, 1H), 7.35-7.21 (m, 3H), 5.54 (s,2H), 3.85 (s, 3H). [M+H]=301.17.

Examples 260-265 were prepared in a manner analogous to Example 259,with the appropriate starting materials and reagent substitutions.

Example 260.[1-({5-[3-(Difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=2.7 Hz, 1H), 7.98 (s, 1H), 7.74 (d,J=2.3 Hz, 1H), 7.47-7.35 (m, 3H), 7.14 (dd, J=1.2, 2.0 Hz, 1H),7.03-6.64 (m, 1H), 5.60 (s, 2H), 4.73-4.60 (m, 2H), 4.41 (d, J=7.0 Hz,2H), 1.34 (t, J=7.0 Hz, 3H). [M+H]=377.25.

Example 261.(1-((6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 7.86 (d,J=2.3 Hz, 1H), 7.61 (t, J=1.0 Hz, 1H), 7.37-7.31 (m, 1H), 7.05 (ddd,J=1.2, 2.5, 3.7 Hz, 2H), 6.95 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 5.67 (s,2H), 4.66 (s, 2H), 4.07 (q, J=6.8 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).[M+H]=377.25.

Example 262.[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98-7.93 (m, 1H),7.88 (t, J=2.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.21 (dd, J=3.5, 8.2 Hz,1H), 7.05-6.65 (m, 1H), 5.73 (s, 2H), 4.67 (s, 2H), 4.51 (q, J=7.0 Hz,2H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=378.24.

Example 263.(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.22 (s, 1H), 8.06-8.02 (m, 2H), 7.99 (ddd,J=1.6, 3.6, 5.4 Hz, 1H), 7.44-7.40 (m, 2H), 5.74 (s, 2H), 4.67 (s, 2H),4.06 (s, 3H). [M+H]=332.15.

Example 264.[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.29 (m, 1H), 8.05 (s, 1H), 7.88-7.84(m, 1H), 7.76-7.72 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.45-7.05 (m, 2H),5.72 (s, 2H), 5.16-5.05 (m, 1H), 4.49 (d, J=5.1 Hz, 2H), 3.98 (s, 3H).[M+H]=364.24.

Example 265.(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.05 (s, 1H), 8.03-8.00 (m,1H), 7.99-7.94 (m, 1H), 7.53-7.49 (m, 2H), 5.71 (s, 2H), 5.16-5.08 (m,1H), 4.50-4.41 (m, 4H), 1.39-1.32 (m, 3H). [M+H]=346.18.

Example 266.3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine

Step 1.1-((5-(3-(Difluoromethoxy)phenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde.To a solution of[1-({5-[3-(difluoromethoxy)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol(Example 260, 115 mg, 0.31 mmol), in DCM (5 mL) was added Dess-MartinReagent® (1.22 mL, 0.30 mol/L, 0.37 mmol). The reaction mixture wasallowed to stir at room temperature for 3 hr. The reaction was quenchedwith wet Na₂SO₄. The reaction mixture was extracted into DCM, filteredand solvent removed under reduced pressure. Purification (FCC, SiO₂,10-100% EtOAc/hexanes) afforded the title compound (90 mg, 79%).

Step 2.3-[3-(Difluoromethoxy)phenyl]-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-ethoxypyridine.To a solution of1-((5-(3-(difluoromethoxy)phenyl)-6-ethoxypyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde(90 mg, 0.24 mmol) in DCM (5 mL) was added Deoxo-Fluor® (133 mg, 0.60mmol). The mixture was stirred at room temperature for 4 h. The materialwas adsorbed on silica. Purification (FCC, SiO₂, 0-80% EtOAc/hexanes)afforded the title compound (53 mg, 56%). ¹H NMR (400 MHz, CD₃OD) δ 8.36(t, J=1.4 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H),7.47-7.36 (m, 3H), 7.16-7.10 (m, 1H), 7.07-6.63 (m, 2H), 5.66 (s, 2H),4.41 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H). [M+H]=397.24.

Example 267.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxylicacid

To a solution of ethyl1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate(Example 168, 25.00 mg, 0.07 mmol) in THF (2 mL), MeOH (2 mL) was addedaq. LiOH (1.00 mL, 1.00 mol/L, 1.00 mmol). The mixture was stirred atroom temperature for 2 h. The solvents were removed under reducedpressure and the crude residue dissolved in water. The aqueous reactionmixture was acidified with 1 N HCl (5 mL), and extracted into ethylacetate. The combined organic layers were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford the title compound (20 mg,87%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (br s, 1H), 8.39 (br s, 1H),8.19 (br s, 1H), 7.80 (br s, 2H), 7.68-7.26 (m, 4H), 5.34 (br s, 2H),3.87 (br s, 3H). [M+H]=344.31.

Example 268.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide

A solution of1-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile(Example 170, 25.00 mg, 0.08 mmol) in MeOH (1.54 mL) was heated to 50°C., until the starting material dissolved. Aq. NaOH (0.23 mL, 1.00mol/L, 0.23 mmol) and H₂O₂ (0.23 mL, 1.00 mol/L, 0.23 mmol) were addedand the reaction stirred at 50° C. for 2 h. Water was added (5 mL), andthe mixture was filtered and washed with water (3×5 mL) to afford thetitle compound as a solid (25.0 mg, 95%). ¹H NMR (400 MHz, DMSO-d₆) δ8.20 (d, J=13.69 Hz, 2H), 7.80 (d, J=14.48 Hz, 2H), 7.65-7.37 (m, 5H),6.95 (br s, 1H), 5.32 (br s, 2H), 3.87 (br s, 3H). [M+H]=343.33.

Example 269.[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol

Step 1.1-((5-(3-(Difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde.The title compound was prepared in a manner analogous to Example 127,with the appropriate starting material substitutions.

Step 2.[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-4-yl]methanol.To a solution of1-((5-(3-(difluoromethoxy)phenyl)-6-methoxypyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde(99 mg, 0.27 mmol) in MeOH (5 mL) was added NaBH₄ (14.3 mg, 0.38 mmol).The mixture was stirred at room temperature for 10 min. The mixture wasquenched with water (0.5 mL), diluted with DCM (10 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification (FCC,SiO₂, 20-100% EtOAc/hexanes) afforded the title compound (100 mg, 100%).¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.3 Hz, 1H), 7.74-7.70 (m, 1H),7.63 (d, J=2.3 Hz, 1H), 7.50 (s, 1H), 7.45-7.34 (m, 2H), 7.30 (t, J=2.3Hz, 1H), 7.13 (s, 1H), 7.03-6.64 (m, 1H), 5.31 (s, 2H), 4.49 (s, 2H),3.94 (s, 3H). [M+H]=362.21.

Examples 270-275 were prepared in a manner analogous to Example 269,with the appropriate starting materials and reagent substitutions.

Example 270.(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-5-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.08-8.30 (m, 1H), 7.92 (d, J=2.35 Hz, 1H),7.77 (s, 1H), 7.57-7.62 (m, 1H), 7.43-7.54 (m, 3H), 6.81 (s, 1H), 5.27(s, 2H), 5.16 (t, J=5.28 Hz, 1H), 4.41 (d, J=5.09 Hz, 2H), 3.49-3.59 (m,2H). [M+H]=366.20.

Example 271.(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.19-8.40 (m, 1H), 8.05 (d, J=2.35 Hz, 1H),7.83-7.46 (m, 6H), 7.13 (s, 1H), 5.20 (s, 2H), 4.28 (s, 2H), 3.55 (s,1H). [M+H]=366.20.

Example 272.[1-({5-[3-(Difluoromethoxy)phenyl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazol-3-yl]methanol

¹H (400 MHz, CD₃OD) δ 8.04 (d, J=2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H),7.47-7.27 (m, 4H), 7.13-7.08 (m, 1H), 7.03-6.63 (m, 1H), 6.29 (d, J=2.0Hz, 1H), 5.40 (s, 2H), 4.65 (s, 2H), 3.92 (s, 3H). [M+H]=362.17.

Example 273.(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.3 Hz, 1H), 7.72 (s, 1H), 7.63 (d,J=2.3 Hz, 1H), 7.55 (t, J=1.6 Hz, 1H), 7.50 (s, 1H), 7.46-7.42 (m, 1H),7.40-7.31 (m, 2H), 5.30 (s, 2H), 4.49 (s, 2H), 4.39 (q, J=7.0 Hz, 2H),1.33 (t, J=7.0 Hz, 3H). [M+H]=344.33.

Example 274.(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, J=2.3 Hz, 1H), 7.80 (s, 1H), 7.68 (d,J=2.3 Hz, 1H), 7.56 (s, 1H), 7.47-7.43 (m, 1H), 7.40-7.31 (m, 2H), 5.25(s, 2H), 4.53 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).[M+H]=378.27.

Example 275.(4-Chloro-1-{[5-(3-chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-pyrazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=2.3 Hz, 1H), 7.68 (d, J=2.3 Hz,1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.46-7.42 (m, 1H), 7.40-7.31 (m, 2H),5.40 (s, 2H), 4.67 (s, 2H), 4.40 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz,4H). [M+H]=378.27.

Example 276.4-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}benzoicacid

The title compound was prepared in a manner analogous to Example 21,with the appropriated starting material and reagent substitutions. ¹HNMR (400 MHz, CD₃OD) δ 8.01 (d, J=2.3 Hz, 1H), 7.87 (d, J=8.2 Hz, 2H),7.63 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.35-7.24 (m, 5H),4.01 (s, 2H). [M+H]=390.09.

Example 277.(1-((6-Ethoxy-5-(2-fluorophenyl)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol

The title compound was prepared in a manner analogous to Intermediate21, from(1-((5-bromo-6-ethoxypyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol(Intermediate 19) and (2-fluorophenyl)boronic acid, substitutingPd(dppf)Cl₂.DCM for Pd(dppf)Cl₂. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s,1H), 8.23 (d, J=2.26 Hz, 1H), 7.69 (d, J=2.26 Hz, 1H), 7.34-7.49 (m,2H), 7.22-7.31 (m, 2H), 5.36 (s, 2H), 5.18 (t, J=6.02 Hz, 1H), 4.38 (d,J=6.02 Hz, 2H), 4.33 (q, J=7.03 Hz, 2H), 1.22 (t, J=7.03 Hz, 3H);[M+H]=329.4.

Example 278.5-((5-(3,4-Difluorophenyl)-6-propoxypyridin-3-yl)methyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Intermediate 21from 5-(chloromethyl)-3-(3,4-difluorophenyl)-2-propoxypyridine(Intermediate 22) and 2-aminopyrimidine-5-boronic acid, substitutingPd(PPh₃)₄ for Pd(dppf)Cl₂. ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 2H),8.07 (d, J=2.35 Hz, 1H), 7.69 (d, J=2.35 Hz, 1H), 7.62-7.68 (m, 1H),7.45-7.53 (m, 1H), 7.39-7.44 (m, 1H), 6.45 (s, 2H), 4.24 (t, J=6.46 Hz,2H), 3.72 (s, 2H), 1.68 (q, J=6.65 Hz, 2H), 0.92 (t, J=7.43 Hz, 3H);[M+H]=357.4.

Example 279.5-((5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Intermediate24, from 5-((5-bromo-6-ethoxypyridin-3-yl)methyl)pyrimidin-2-amine(Intermediate 52) and (3-chloro-4-fluorophenyl)boronic acid,substituting aq. NaHCO₃ for Na₂CO₃. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s,2H), 8.08 (d, J=2.3 Hz, 1H), 7.77 (dd, J=2.2, 7.2 Hz, 1H), 7.71 (d,J=2.3 Hz, 1H), 7.58 (ddd, J=2.2, 4.9, 8.6 Hz, 1H), 7.49-7.42 (m, 1H),4.33 (q, J=7.0 Hz, 2H), 3.76 (s, 2H), 1.26 (t, J=7.0 Hz, 3H);[M+H]=359.25.

Example 280. 2-(4-((5-(3-Chlorohenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide

Step 1.2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)aceticacid. To a solution of2-(4-((5-(3,4-difluorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetate(Intermediate 50, 100.00 mg, 0.25 mmol) in THF (1.26 mL) and MeOH (1.3mL) was added 1N solution of LiOH (0.63 mL, 0.25 mmol). The reactionmixture stirred at room temperature for 30 min. EtOAc (10 mL) was addedto the reaction mixture followed by sat. aq. NaHCO₃ (10 mL). The aqueouslayer was extracted and acidified with conc. HCl. The acidified aq.layer was extracted with EtOAc (10 mL), and the combined organic layerswere collected, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The title compound was used crude in the next step withoutfurther purification.

Step 2.2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetylchloride. To a solution of2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)aceticacid in DCM (2.0 mL) was added oxalyl chloride (0.25 mL, 0.50 mmol). Thereaction mixture was stirred at room temperature for 30 min, and thesolvent was removed under reduced pressure. The crude title compound wasused in the next step without further purification.

Step 3.2-(4-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetamide.A solution of2-(4-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)phenyl)acetylchloride in 4N ammonia in dioxane (0.75 mL, 0.75 mmol) was stirred atroom temperature for 30 min. The reaction mixture was concentrated andthe precipitate was filtered and washed with water to obtain the titlecompound (60 mg, 64%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.10(d, J=2.3 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.60-7.56 (m, 1H), 7.51-7.33(m, 4H), 7.25-7.11 (m, 4H), 6.81 (br s, 1H), 3.90 (s, 2H), 3.85 (s, 3H),3.30 (s, 2H); [M+H]=367.40.

Example 281.2-(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

H₂SO₄ (1 mL) was added to2-(5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile(Intermediate 53, 100 mg, 0.30 mmol) and the reaction stirred at roomtemperature for 1 h. The reaction mixture was cooled in an ice bath, icewas added to the reaction mixture, followed by water (100 mL), andstirred for 30 min. Solids were filtered, and the pH of the aq. layeradjusted to neutral with aq. NaHCO₃. The aq. layer was extracted withDCM, the combined organic layers were dried (Na₂SO₄), filtered andconcentrated onto silica gel. Purification (FCC, SiO₂, 10% MeOH/90%EtOAc) afforded the title compound (60 mg, 57%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.69 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H),7.61-7.49 (m, 4H), 7.29-7.18 (m, 4H), 3.94 (s, 2H), 3.83 (s, 5H), 3.66(s, 2H); [M+H]=353.25.

Example 282.5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

The title compound was prepared in a manner analogous to Example 13 from5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ8.88 (s, 2H), 8.18 (d, J=2.3 Hz, 1H), 8.10(br s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.75 (dd, J=2.2, 7.2 Hz, 1H), 7.71(br s, 1H), 7.58-7.52 (m, 1H), 7.49-7.39 (m, 1H), 4.05 (s, 2H), 3.85 (s,3H); [M+H]=373.10.

Example 283.2-[(5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol

The title compound was prepared in manner analogous to Example 3,employing2-Chloro-5-((5-(4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine(Intermediate 51). ¹H NMR (400 MHz, DMSO-d₆) δ8.20 (s, 2H), 8.06 (d,J=2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.28-7.19 (m,2H), 6.86 (t, J=5.9 Hz, 1H), 4.65-4.57 (m, 1H), 3.83 (s, 3H), 3.71 (s,2H), 3.45 (q, J=6.1 Hz, 2H), 3.27 (q, J=6.5 Hz, 2H); [M+H]=355.25.

Example 284.2-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)-2-methylpropanenitrile

To a cooled 0° C. mixture of2-(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)acetonitrile(100.00 mg, 0.29 mmol), DMSO (2.85 mL), water (0.40 mL) and NaOH (45.6mg, 1.14 mmol) was added MeI (0.070 mL, 1.14 mmol) dropwise. Theresultant mixture was stirred at rt for 40 min. before being poured intowater (10 mL). The precipitate was filtered and washed with water toobtain the title compound (85 mg, 78%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.85-8.81 (m, 2H), 8.17 (d, J=2.3 Hz, 1H), 7.80 (d,J=2.3 Hz, 1H), 7.61-7.59 (m, 1H), 7.53-7.48 (m, 1H), 7.47-7.38 (m, 2H),3.99 (s, 2H), 3.85 (s, 3H), 1.68 (s, 7H); [M+H]=379.40.

Example 285.2-(1-{[5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetonitrile

Step 1.5-((3-(Chloromethyl)-1H-1,2,4-triazol-1-yl)methyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine.To a solution of(1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol(Example 199, 200 mg, 0.55 mmol) in DCM (15 mL) was addedthionylchloride (97.32 mg, 0.82 mmol). The mixture was stirred at rt for1 hr. The solvent was removed under reduced pressure to afford a whitesolid which was used without further purification in the following step.

Step 2.2-(1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)acetonitrile.To a solution of5-((3-(chloromethyl)-1H-1,2,4-triazol-1-yl)methyl)-3-(3-chlorophenyl)-2-(difluoromethoxy)pyridine(201 mg, 0.52 mmol) in DMF (1 mL) was added Cs₂CO₃ (510 mg, 1.572 mmol)followed by KCN (50.97 mg, 0.78 mmol). The mixture was stirred at rt for3 h. The reaction mixture was diluted with water and extracted intoEtOAc. The combined organic fractions were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. Purification (FCC, SiO₂, 30-90%,EtOAc/hexanes) afforded the title compound (165 mg, 84%). ¹H NMR (400MHz, CD₃OD) δ 8.58 (s, 1H), 8.26 (s, 1H), 7.94 (d, J=2.3 Hz, 1H),7.81-7.61 (m, 1H), 7.58-7.55 (m, 1H), 7.48-7.41 (m, 3H), 5.47-5.46 (m,2H), 4.01-3.97 (m, 2H); [M+H]=376.

Example 286.3-(3-Chlorophenyl)-5((5-ethoxypyridin-2-yl)methyl)-2-methoxy pyridine

The title compound was prepared in a manner analogous to Intermediate 55employing3-(3-chlorophenyl)-2-methoxy-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)pyridine(Intermediate 31) and 2-bromo-5-ethoxypyridine. ¹H NMR (400 MHz, CDCl₃)δ 8.24 (d, J=2.35 Hz, 1H), 8.07 (d, J=1.96 Hz, 1H), 7.52 (s, 1H), 7.49(d, J=1.96 Hz, 1H), 7.38-7.43 (m, 1H), 7.29-7.36 (m, 2H), 7.10-7.16 (m,1H), 7.04-7.09 (m, 1H), 4.02-4.11 (m, 4H), 3.96 (s, 3H), 1.42 (t, J=7.04Hz, 3H); [M+H]=355.3.

Example 287.5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine

tert-Butyl(5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate(Intermediate 55) was dissolved in DCM (5 mL)/TFA (1 mL) and stirred atrt for 4 hrs. The reaction mixture was concentrated under reducedpressure. After evaporating the solvent, the material was dissolved inEtOAc, washed with sat. aq. NaHCO₃. The organics were dried (Na₂SO₄),filtered, and concentrated under reduced pressure to provide the titlecompound as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=2.35 Hz,1H), 7.89 (s, 2H), 7.60 (d, J=2.35 Hz, 1H), 7.53 (t, J=1.96 Hz, 1H),7.40-7.44 (m, 1H), 7.37 (t, J=7.43 Hz, 1H), 7.30-7.34 (m, 1H), 3.95 (s,2H), 3.92 (s, 3H); [M+H]=327.3.

Example 288.5-((5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to Example 291. ¹HNMR (400 MHz, CD₃OD) δ 8.07 (d, J=2.35 Hz, 1H), 8.05 (s, 1H), 7.80 (s,1H), 7.57 (dd, J=2.35, 7.04 Hz, 1H), 7.46 (d, J=2.35 Hz, 1H), 7.39 (ddd,J=2.35, 4.70, 8.61 Hz, 1H), 7.17 (t, J=8.61 Hz, 1H), 3.98 (s, 2H), 3.96(s, 3H); [M+H]=345.32.

Example 289.2-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-5-ethoxypyrazine

To a solution of5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-amine(Example 287, 39 mg, 0.12 mmol) in EtOH (3 mL) was added tert-butylnitrite (48 μL, 0.36 mmol) followed by 4 N HCl in dioxane (6 μL, 4.00mol/L, 0.02 mmol). The resulting solution was stirred at rt overnight.The reaction mixture was concentrated under reduced pressure and theresidue was partitioned between DCM/sat NaHCO₃. The organic layer dried(Na₂SO₄), filtered, and concentrated under reduced pressure to afford ayellow oil. Purification (prep TLC, SiO₂, hexanes/EtOAc (8:2)) providedthe title compound as a colorless oil (19.7 mg, 47%). ¹H NMR (400 MHz,CD₃OD) δ 8.15 (d, J=1.17 Hz, 1H), 8.09 (d, J=2.35 Hz, 1H), 7.97 (d,J=1.57 Hz, 1H), 7.52 (t, J=1.76 Hz, 1H), 7.50 (d, J=2.35 Hz, 1H),7.39-7.43 (m, 1H), 7.30-7.35 (m, 2H), 4.35 (q, J=7.04 Hz, 2H), 4.04 (s,2H), 3.96 (s, 3H), 1.40 (t, J=7.24 Hz, 3H); [M+H]=356.31.

Example 290.2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)amino)ethanol

A solution consisting of2-bromo-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazine(Intermediate 57, 37.5 mg, 0.10 mmol) and 2-aminoethanol (23 μL, 0.38mmol) in dioxane (2 mL) and n-butanol (1 mL) was heated at 175° C.overnight. The solvent was removed under reduced pressure and the cruderesidue purified by preparative HPLC using a 15-85% gradient withformate as the additive. Addition of concentrated NH₄OH followed byevaporation of the solvent gave the desired compound as a white solid(19 mg, 47%). ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=2.35 Hz, 1H), 7.92(d, J=1.17 Hz, 1H), 7.88 (d, J=1.17 Hz, 1H), 7.60 (d, J=2.35 Hz, 1H),7.53 (t, J=1.76 Hz, 1H), 7.41-7.45 (m, 1H), 7.35-7.40 (m, 1H), 7.31-7.35(m, 1H), 3.94 (s, 2H), 3.92 (s, 3H), 3.69 (t, J=5.67 Hz, 2H), 3.45 (t,J=5.67 Hz, 2H); [M+H]=371.32.

Example 291.3-(3-Chlorophenyl)-2-methoxy-5-((5-methyl-1H-tetrazol-1-yl)methylpyridine

The title compound was prepared in a manner analogous to Intermediate 32employing 5-(chloromethyl)-3-(3-chlorophenyl)-2-methoxypyridine(Intermediate 30) and 5-methyl-2H-tetrazole. ¹H NMR (400 MHz, CD₃OD) δ8.26 (d, J=2.35 Hz, 1H), 7.65 (d, J=2.74 Hz, 1H), 7.52 (q, J=1.57 Hz,1H), 7.32-7.42 (m, 3H), 5.69 (s, 2H), 3.98 (s, 3H), 2.53 (s, 3H);[M+H]=316.36.

Example 292.4-(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)pyrimidin-2-yl)morpholine

A mixture of2-chloro-5-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine(Example 2, 73 mg, 0.21 mmol), DIEA (184 μL, 1.06 mmol) and morpholine(73.17 μL, 0.85 mmol) in dioxane (2 mL) was heated at 110° C. for 24 h.The dioxane was removed under reduced pressure and the residue taken upin MeOH (2 mL) before being purified. Purification (Preparative HPLC,15-85% gradient with formic acid in the mobile phase) provided the titlecompound as a white solid (48 mg, 57%). ¹H NMR (400 MHz, CD₃OD) d 8.27(s, 2H), 8.03 (d, J=2.35 Hz, 1H), 7.55 (d, J=2.35 Hz, 1H), 7.52-7.54 (m,1H), 7.40-7.44 (m, 1H), 7.35-7.40 (m, 1H), 7.31-7.35 (m, 1H), 3.93 (s,3H), 3.83 (s, 2H), 3.72 (s, 8H); [M+H]=397.42.

Example 293.5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-amine

A mixture of 5-(bromomethyl)-3-(3,4-difluorophenyl)-2-ethoxypyrazine(Intermediate 46, 91 mg, 0.28 mmol), Pd(PPh₃)₄ (26 mg, 0.02 mmol), K₂CO₃(115 mg, 0.83 mmol) and 2-aminopyrimidine-5-boronic acid (58 mg, 0.41mmol) in dioxane (2 mL) and water (500.00 μL) was heated employingmicrowave irradiation at 130° C. for 30 min. Purification (preparativeHPLC, 15-85% gradient with formic acid as the additive) afforded thetitle compound as a white solid (29 mg, 31%). ¹H NMR (400 MHz, CD₃OD) d8.29 (s, 2H), 8.06 (s, 1H), 7.95-8.06 (m, 2H), 7.32 (td, J=8.56, 10.27Hz, 1H), 4.49 (q, J=7.04 Hz, 2H), 3.97 (s, 2H), 1.44 (t, J=7.04 Hz, 3H);[M+H]=344.41.

Example 294.2-((5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidin-2-yl)amino)ethanol

A mixture consisting of2-chloro-5-((6-(3,4-difluorophenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine (Intermediate 48, 59.10 mg, 0.16 mmol) in 2-aminoethanol (1mL) was heated at 100° C. for 2 h. The mixture was poured into H₂0 (10mL) and let sit at rt overnight. The reaction mixture was filtered, andthe collected solid was purified (preparative HPLC, 15-85% gradient withformic acid as additive). Treatment with concentrated NH₄OH andevaporation gave the desired compound as a white solid (37 mg, 58%). ¹HNMR (400 MHz, CD₃OD) d 8.51 (s, 1H), 8.30 (s, 2H), 8.06-8.07 (m, 1H),7.95-8.05 (m, 2H), 7.33 (td, J=8.61, 10.56 Hz, 1H), 4.50 (q, J=7.04 Hz,2H), 3.97 (s, 2H), 3.65-3.72 (m, 2H), 3.44-3.52 (m, 2H), 1.44 (t, J=7.04Hz, 3H); [M+H]=388.46.

Example 295.2-(1-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)ethanol

To a solution of ethyl2-(2-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)-1H-tetrazol-5-yl)acetate(Intermediate 33, 49.30 mg, 0.13 mmol) in THF (5 mL) at 0° C. was addedLAH (69 μL, 2.40 mol/L, 0.17 mmol). The resulting solution was allowedto warm to rt over 3 h then carefully quenched by adding dropwise asolution of KF (37 mg, 0.64 mmol) dissolved in water (1 mL). Thereaction mix was stirred for 15 min then filtered thru a bed of Celite®.The Celite® was washed throughly with EtOAc, and the EtOAC washes wereconcentrated under reduced pressure. Purification (preparative HPLC,15-85% gradient with formic acid as additive) afforded the titlecompound as a colorless oil (1 mg, 3%). ¹H NMR (400 MHz, CDCl₃) δ 8.16(d, J=2.35 Hz, 1H), 7.55 (d, J=2.35 Hz, 1H), 7.49-7.52 (m, 1H), 7.36 (d,J=1.17 Hz, 3H), 5.54 (s, 2H), 4.12 (t, J=5.09 Hz, 2H), 3.99 (s, 3H),3.01-3.09 (m, 2H).

Example 296.2-Ethoxy-3-(4-fluorophenyl)-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine

The title compound was prepared in a manner analogous to Intermediate21, employing3-bromo-2-ethoxy-5-((5-methyl-1H-tetrazol-1-yl)methyl)pyridine(Intermediate 32) and (4-fluorophenyl)boronic acid, in dioxane/water. ¹HNMR (400 MHz, CDCl₃) δ 8.10 (d, J=2.35 Hz, 1H), 7.44-7.53 (m, 3H),7.06-7.14 (m, 2H), 5.46 (s, 2H), 4.43 (q, J=7.04 Hz, 2H), 2.56 (s, 3H),1.37 (t, J=7.04 Hz, 3H); [M+H]=314.43.

Example 297.2′-(Difluoromethoxy)-5-((4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl)methyl)-2-methoxy-3,4′-bipyridine

Step 1.1-((2′-(difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-2-methyl-1H-imidazole-4-carbaldehyde.A solution of5-(chloromethyl)-2′-(difluoromethoxy)-2-methoxy-3,4′-bipyridine(Intermediate 42, 300 mg, 1.0 mmol),2-methyl-1H-imidazole-4-carbaldehyde (109.8 mg, 1.0 mmol), Cs₂CO₃ (487.6mg, 1.5 mmol) and acetone (5 mL) were stirred at rt for 3 h. Thereaction mixture was diluted with DCM, filtered, and the organics wereremoved under reduced pressure. Purification (FCC, SiO₂, 10%MeOH/DCM/EtOAc) provided the title compound as a mixture of tworegioisomers (60 mg, 16%).

Step 2.5-((2′-(Difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine.The title compound was prepared in a manner analogous to Example 256Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.25-8.21 (m, 1H), 8.12 (d, J=2.3 Hz,1H), 7.75-7.72 (m, 1H), 7.58-7.35 (m, 3H), 7.18 (d, J=0.8 Hz, 1H), 6.62(s, 1H), 5.21 (s, 2H), 3.98 (s, 3H), 2.40 (s, 3H); [M+H]=397.

Example 298.2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide

Step 1. Methyl2-((5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetate.To a solution of methyl glycolate (106.47 mg, 1.18 mmol) in toluene (5mL) was added 60% NaH in mineral oil (35 mg, 0.89 mmol). The solutionwas stirred under nitrogen at 0° C. for 30 min. then[2-chloro-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine](Example 2, 204.60 mg, 0.59 mmol) was added. The reaction mixture wasstirred at 60° C. for 18 h. Additional NaH (20 mg, 0.51 mmol) was added,and the reaction mixture was heated an additional 8 h. The reaction mixwas cooled in an ice water bath and 1M NH₄Cl was added. The crudereaction mixture was extracted with EtOAc. The combined organic phasewas treated with brine, dried (Na₂SO₄), filtered and concentrated toafford (224.5 mg, 95%) of the title compound as an oil. [M+H]=400.39.

Step 2.2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)acetamide.The title compound was prepared in a manner analogous to Example 240. ¹HNMR (400 MHz, DMSO-d₆) δ 8.55 (s, 2H), 8.13 (d, J=2.35 Hz, 1H), 7.74 (d,J=2.35 Hz, 1H), 7.59 (t, J=1.57 Hz, 1H), 7.35-7.53 (m, 4H), 7.12 (br s,1H), 4.65 (s, 2H), 3.89 (s, 2H), 3.55 (s, 1H), 3.30 (s, 3H);[M+H]=385.38.

Example 299.(5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)methanol

To a cooled, 0° C., solution of methyl5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine-2-carboxylate(Intermediate 44, 277 mg, 0.75 mmol) in MeOH (4 mL), was added NaBH₄ (28mg, 0.75 mmol). The reaction mixture was stirred at 0° C. for anadditional 8 h then neutralized to pH 7 with 1M aq. citric acid andextracted with EtOAc. The combined organics were dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification (FCC,SiO₂, hexanes/(10% MeOH in EtOAc) 0-100%) afforded (64 mg, 25%) of thetitle compound as a light yellow semi-solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.74 (s, 2H), 8.16 (d, J=2.35 Hz, 1H), 7.75 (d, J=2.35 Hz, 1H),7.54-7.64 (m, 1H), 7.33-7.54 (m, 3H), 5.12-5.23 (m, 1H), 4.54 (d, J=6.26Hz, 2H), 3.96 (s, 2H), 3.85 (s, 3H); [M+H]=342.40.

Example 300.(1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol

Step 1. Methyl1-((5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate.The title compound was prepared in a manner analogous to Example 127from5-(chloromethyl)-3-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyridine.[M+H]=427.35.

Step 2.(1-((5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-yl)methanol.To a cooled, 0° C., solution of methyl1-((5-(3-chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate(172.30 mg, 0.40 mmol) in THF (5 mL), under nitrogen was added DIBAL(0.81 mL, 1.00 mol/L, 0.81 mmol) over 1 min. The ice bath was removed,and the reaction mixture was stirred at rt for 3.5 h. The reactionmixture was concentrated then re-dissolved in DCM (5 mL), and 1N NaOHaq. (0.5 mL) was added. The solution was stirred for an additional 8 hat rt. The layers were separated and the aq. phase was extracted withDCM. The combined organic phase was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. (FCC, SiO₂, 0-10% DCM/MeOH)afforded the title compound (25 mg, 16%) as a white powder. ¹H NMR (400MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.22 (d, J=2.3 Hz, 1H) 7.95 (d, J=2.3 Hz,1H), 7.55-7.41 (m, 1H), 5.39 (s, 1H), 5.03 (q, J=9.0 Hz, 1H), 4.36 (d,J=6.3 Hz, 1H), 3.30 (s, 2H), 2.48 (td, J=1.9, 3.6 Hz, 4H); [M+H]=399.35.

Example 301.5-((2′-(Difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine

Step 1.5-((2′-(Difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoro-N-(4-methoxybenzyl)pyridin-2-amine.The title compound was prepared in a manner analogous to Example 3 usingIntermediate 58. [M+H]=497.52.

Step 2.5-((2′-(Difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoropyridin-2-amine.A solution of5-((2′-(difluoromethoxy)-2-methoxy-[3,4′-bipyridin]-5-yl)methyl)-3-fluoro-N-(4-methoxybenzyl)pyridin-2-amine(90.7 mg, 0.18 mmol) in TFA (5 mL) was heated 50° C. for 8 h. Thereaction mixture was concentrated and re-dissolved in EtOAc then washedwith NaHCO₃. The organics were separated, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-100%EtOAc/hexanes) afforded (6.14 mg, 9%) of the title compound as a tansolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=5.4 Hz, 1H), 8.18 (d,J=2.2 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.78-7.55 (m, 2H), 7.49 (dd,J=1.3, 5.3 Hz, 1H), 7.30 (s, 2H), 6.02 (s, 2H), 3.89 (s, 3H), 3.80 (s,2H); [M+H]=377.20.

Example 302.5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol

To a cooled, 0° C., solution of5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-amine(Example 25, 104 mg, 0.32 mmol), in DMF (5 mL) and water (5 mL) wasadded tert-butyl nitrite (150 μL, 1.27 mmol). The reaction mixture wasallowed to warm up to rt and stirred for an additional 7 h. The rxnmixture was diluted with water and extracted with EtOAc. The combinedorganic phase was treated with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-15%MeOH/DCM) afforded the title compound as a white solid (80.48 mg, 77%).¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.19 (br s, 1H), 8.11 (d,J=2.35 Hz, 1H), 7.71 (d, J=2.35 Hz, 1H), 7.59 (t, J=1.57 Hz, 1H),7.32-7.56 (m, 3H), 3.69 (s, 3H), 3.55 (s, 2H); [M+H]=326.26.

Example 303.2-((5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-yl)oxy)ethanol

To a cooled, 0° C., solution of ethylene glycol (4.0 mL) was added NaH(10.40 mg, 0.43 mmol). The solution was stirred under nitrogen at 0° C.for 30 min. then2-chloro-5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidine(Example 2, 100.00 mg, 0.29 mmol) was added. The reaction mixture wasallowed to warm to rt and stirred for an additional 8 h. The rxn mixturewas diluted with water to obtain a ppt, which was washed with diethylether and dried (Na₂SO₄), filtered, and concentrated under reducedpressure to afford (41 mg, 37%) of the title compound as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 2H), 8.13 (d, J=2.35 Hz, 1H), 7.72(d, J=2.35 Hz, 1H), 7.54-7.65 (m, 1H), 7.35-7.54 (m, 3H), 4.83 (t,J=5.48 Hz, 1H), 4.18-4.30 (m, 2H), 3.79-3.93 (m, 4H), 3.60-3.74 (m, 2H);[M+H]=372.38

Example 304.5-((5-(3-Chlorophenyl)-6-methoxypyridin-3-yl)methyl)-2-(difluoromethoxy)pyrimidine

To a solution of5-((5-(3-chlorophenyl)-6-methoxypyridin-3-yl)methyl)pyrimidin-2-ol(Example 306, 248.20 mg, 0.76 mmol) in ACN (5 mL) was added2,2-difluoro-2-(fluorosulfonyl)acetic acid (87.26 μL, 0.83 mmol) andNa₂CO₃ (160.52 mg, 1.51 mmol). The suspension was stirred at rt for 48h. The reaction mixture was filtered, diluted with EtOAc and washed withwater. The organic phase was treated with brine, dried (Na₂SO₄),filtered and concentrated. Purification (FCC, SiO₂, 0-30% EtOAc/hexanes)afforded the title compound as a colorless oil (17 mg, 6%). ¹H NMR (400MHz, CDCl₃) δ 8.45 (s, 2H), 8.04 (d, J=2.35 Hz, 1H), 7.49 (t, J=36 Hz,1H), 7.29-7.22 (m, 5H), 3.96 (s, 3H), 3.93 (s, 2H); [M+H]=378.35.

Examples 305-306 were prepared in a manner analogous to Example 1, withthe appropriate starting material and reagent substitutions.

Example 305.5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-3-methylpyridazine

¹H NMR (400 MHz, CD₃OD) δ 8.97 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.7 Hz,1H), 7.63 (d, J=2.3 Hz, 1H), 7.55 (s, 1H), 7.49-7.31 (m, 4H), 4.07-4.03(m, 2H), 3.95 (s, 3H), 2.65-2.61 (m, 3H); [M+H]=326.

Example 306.3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-fluoropyridin-3-yl)methyl]pyridine

¹H NMR (400 MHz, CD₃OD) δ 8.39-8.35 (m, 1H), 8.34-8.31 (m, 1H),8.23-8.19 (m, 1H), 8.12 (s, 1H), 7.77-7.73 (m, 1H), 7.57-7.19 (m, 4H),4.47-4.38 (m, 2H), 4.11-4.05 (m, 2H), 1.36 (s, 3H); [M+H]=376.

Examples 307-314 were prepared in a manner analogous to Example 127,with the appropriate starting material and reagent substitutions.

Example 307.1-{[5-(2-Cyanopyridin-4-yl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.75-8.85 (m, 1H), 8.22-8.34 (m, 2H), 8.02(d, J=2.35 Hz, 1H), 7.86-7.99 (m, 2H), 7.42 (br s, 1H), 7.18 (br s, 1H),6.62 (d, J=2.35 Hz, 1H), 5.38 (s, 2H), 3.91 (s, 3H); [M+H]=335.37.

Example 308.1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-pyrazole-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.3 Hz,1H), 7.78 (d, J=2.3 Hz, 1H), 7.59-7.56 (m, 1H), 7.50-7.40 (m, 4H),7.22-7.16 (m, 1H), 6.61 (d, J=2.3 Hz, 1H), 5.39-5.34 (m, 2H), 3.87 (s,3H); [M+H]=343.

Example 309.1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-1H-pyrazole-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.26-8.20 (m, 2H), 7.88-7.77 (m, 2H),7.75-7.55 (m, 1H), 7.41-7.36 (m, 1H), 7.18 (dd, J=0.8, 1.6 Hz, 1H), 6.76(s, 1H), 5.41 (s, 2H), 3.98 (s, 3H); [M+H]=376.

Example 310.1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-imidazole-4-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=2.3 Hz, 1H), 7.57 (d, J=1.6 Hz,1H), 7.52-7.48 (m, 2H), 7.41 (d, J=2.3 Hz, 1H), 7.40-7.29 (m, 3H),7.03-6.87 (m, 1H), 5.71-5.58 (m, 1H), 5.09 (s, 2H), 4.43 (d, J=7.0 Hz,2H), 1.37 (t, J=7.0 Hz, 3H); [M+H]=357.

Example 311.1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-1H-imidazole-4-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.27-8.21 (m, 2H), 7.86-7.81 (m, 2H),7.75-7.56 (m, 2H), 7.43-7.40 (m, 1H), 5.33-5.25 (m, 2H), 4.50-4.41 (m,2H), 1.41-1.33 (m, 3H); [M+H]=390.

Example 312.1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-arboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.18 (s, 1H), 8.10-8.06 (m, 1H), 8.04-7.98 (m,1H), 7.89-7.85 (m, 1H), 7.80 (s, 1H), 7.43 (s, 2H), 5.39 (s, 2H),4.58-4.47 (m, 2H), 1.44 (s, 3H); [M+H]=358.

Example 313.1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-pyrazole-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.07 (m, 2H), 8.02-7.97 (m, 1H), 7.87-7.84 (m,1H), 7.43-7.40 (m, 2H), 6.81-6.77 (m, 1H), 5.52 (s, 2H), 4.49 (q, J=7.0Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); [M+H]=358.

Example 314.1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 1H), 8.04 (s, 2H), 7.90-7.78 (m, 2H),7.33 (td, J=8.6, 10.3 Hz, 1H), 5.38 (s, 2H), 4.58-4.49 (m, 2H), 1.45 (s,3H); [M+H]=360.

Examples 315-316 were prepared in a manner analogous to Example 198,with the appropriate starting material and reagent substitutions.

Example 315.[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-2-methyl-1H-imidazol-4-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.25-8.21 (m, 1H), 8.11 (d, J=2.3 Hz, 1H),7.76-7.55 (m, 2H), 7.38 (dd, J=1.4, 5.3 Hz, 1H), 7.17 (dd, J=0.8, 1.6Hz, 1H), 7.02 (s, 1H), 5.21-5.13 (m, 2H), 4.47-4.42 (m, 2H), 3.98 (s,3H), 2.36 (s, 3H); [M+H]=377.

Example 316.[1-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)-5-methyl-1H-pyrazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.23-8.20 (m, 1H), 8.05-8.02 (m, 1H), 7.56 (s,2H), 7.38-7.35 (m, 1H), 7.18-7.14 (m, 1H), 6.20-6.11 (m, 1H), 5.28 (s,2H), 4.51 (s, 2H), 3.96 (s, 3H), 2.30 (d, J=0.8 Hz, 3H); [M+H]=377.

Example 317.1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-amine

The title compound was prepared in a manner analogous to Example 219,with the appropriate starting material and reagent substitutions. ¹H NMR(400 MHz, CD₃OD) δ 7.90 (d, J=2.3 Hz, 1H), 7.54 (t, J=2.0 Hz, 1H), 7.48(d, J=2.3 Hz, 1H), 7.45-7.41 (m, 1H), 7.40-7.31 (m, 2H), 5.49 (d, J=0.8Hz, 1H), 5.07 (s, 2H), 4.38 (d, J=7.0 Hz, 2H), 2.21 (s, 3H), 1.33 (t,J=7.0 Hz, 3H); [M+H]=343.

Example 318.1-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)oxy]-2-methylpropan-2-ol

The title compound was prepared in a manner analogous to Example 245,with the appropriate starting material and reagent substitutions. ¹H NMR(400 MHz, DMSO-d₆) δ 8.53 (s, 2H), 8.13 (d, J=2.35 Hz, 1H), 7.72 (d,J=2.35 Hz, 1H), 7.36-7.65 (m, 4H), 4.62 (s, 1H), 4.01 (s, 2H), 3.85 (s,3H), 3.55 (s, 2H), 1.15 (s, 6H); [M+H]=400.43.

Examples 319-326 were prepared in a manner analogous to Example 269,with the appropriate starting material and reagent substitutions.

Example 319.(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 7.87 (d, J=2.3 Hz, 1H), 7.56-7.30 (m, 5H),6.85 (s, 1H), 5.27 (s, 2H), 4.53 (s, 2H), 4.39 (d, J=7.0 Hz, 2H), 2.31(s, 3H), 1.33 (t, J=7.0 Hz, 3H); [M+H]=358.

Example 320.(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-3-methyl-1H-pyrazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, J=2.3 Hz, 1H), 7.60 (d, J=2.3 Hz,1H), 7.55 (s, 1H), 7.46-7.30 (m, 3H), 6.10-6.05 (m, 1H), 5.29 (s, 2H),4.59 (s, 2H), 4.38 (d, J=7.0 Hz, 2H), 2.20 (s, 3H), 1.33 (s, 3H);[M+H]=358.

Example 321.(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.10-8.06 (m, 1H), 7.80-7.42 (m, 6H),7.06-7.02 (m, 1H), 5.24-5.21 (m, 2H), 4.48-4.44 (m, 2H), 2.36 (s, 3H);[M+H]=380.

Example 322.(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CDCl₃) δ 7.99-7.96 (m, 1H), 7.88 (ddd, J=1.6, 3.6, 5.4Hz, 1H), 7.75 (s, 1H), 7.31 (d, J=1.2 Hz, 2H), 6.84-6.79 (m, 1H), 5.03(s, 2H), 4.49-4.38 (m, 2H), 3.94 (s, 3H), 2.36 (s, 3H); [M+H]=345.

Example 323.(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.10-8.06 (m, 1H), 8.05-7.97 (m, 1H), 7.90 (s,1H), 7.45-7.40 (m, 2H), 6.19-6.13 (m, 1H), 5.37 (s, 2H), 4.55-4.44 (m,4H), 2.42 (d, J=0.8 Hz, 3H), 1.43 (t, J=7.0 Hz, 3H); [M+H]=359.

Example 324.(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.05 (m, 3H), 7.45-7.40 (m, 2H), 7.08-7.02 (m,1H), 5.24 (s, 2H), 4.56-4.47 (m, 2H), 4.46-4.43 (m, 2H), 2.45 (s, 3H),1.44 (t, J=7.0 Hz, 3H); [M+H]=359.38.

Example 325.(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=2.3 Hz, 1H), 7.57-7.50 (m, 2H),7.45-7.31 (m, 3H), 6.13 (s, 1H), 5.27 (s, 2H), 4.51 (s, 2H), 4.39 (d,J=7.0 Hz, 2H), 2.30 (d, J=0.8 Hz, 3H), 1.33 (s, 3H); [M+H]=358.

Example 326.(1-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J=2.3 Hz, 1H), 7.57-7.53 (m, 2H),7.46-7.32 (m, 3H), 7.01 (s, 1H), 5.16-5.11 (m, 2H), 4.44 (d, J=0.8 Hz,4H), 2.36 (s, 3H), 1.34 (s, 4H); [M+H]=358.

Examples 327-346 were prepared in a manner analogous to Example 277,with the appropriate starting material and reagent substitutions.

Example 327.(1-{[6-Ethoxy-5-(3-methoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.15 (d, J=2.3 Hz, 1H), 7.76(d, J=2.3 Hz, 1H), 7.36-7.29 (m, 1H), 7.13-7.05 (m, 2H), 6.94-6.88 (m,1H), 5.41-5.38 (m, 1H), 5.35 (s, 2H), 4.39-4.21 (m, 4H), 3.76 (s, 3H),1.27 (t, J=7.0 Hz, 3H); [M+H]=341.37.

Example 328.(1-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.76(d, J=2.3 Hz, 1H), 7.60-7.54 (m, 2H), 7.52-7.45 (m, 2H), 5.34 (s, 2H),4.41-4.24 (m, 5H), 1.26 (t, J=7.0 Hz, 3H); [M+H]=345.12.

Example 329.(1-{[5-(5-Chloropyridin-3-yl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 8.24(d, J=2.3 Hz, 1H), 8.14-8.11 (m, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.94 (d,J=2.3 Hz, 1H), 5.36 (s, 2H), 4.43-4.26 (m, 7H), 1.29-1.24 (m, 3H);[M+H]=346.25.

Example 330.(1-{[5-(3,4-Dichlorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.85(d, J=2.3 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H),7.59-7.53 (m, 2H), 5.34 (s, 2H), 5.15 (t, J=6.1 Hz, 1H), 4.41-4.30 (m,4H), 1.27 (t, J=7.0 Hz, 3H); [M+H]=379.25.

Example 331.(1-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.73(d, J=2.3 Hz, 1H), 7.46-7.32 (m, 2H), 7.18 (dd, J=8.4, 9.6 Hz, 1H), 5.34(s, 2H), 4.43-4.22 (m, 4H), 2.26 (d, J=2.0 Hz, 3H), 1.26 (t, J=7.0 Hz,3H); [M+H]=343.25.

Example 332.[1-({6-Ethoxy-5-[3-(trifluoromethyl)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.21 (d, J=2.3 Hz, 1H),7.94-7.83 (m, 3H), 7.75-7.61 (m, 2H), 5.36 (s, 2H), 4.44-4.27 (m, 6H),1.26 (t, J=7.0 Hz, 3H); [M+H]=379.20.

Example 333.[1-({6-Ethoxy-5-[3-(trifluoromethoxy)phenyl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.84(d, J=2.3 Hz, 1H), 7.63-7.51 (m, 3H), 7.40-7.29 (m, 1H), 5.35 (s, 2H),4.44-4.18 (m, 6H), 1.27 (t, J=7.0 Hz, 3H); [M+H]=395.25.

Example 334.(1-{[6-Ethoxy-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.75(d, J=2.3 Hz, 1H), 7.36-7.28 (m, 1H), 7.12-7.02 (m, 2H), 6.90 (ddd,J=1.2, 2.3, 8.2 Hz, 1H), 5.34 (s, 2H), 4.40-4.29 (m, 4H), 4.04 (q, J=7.0Hz, 2H), 1.32 (t, J=6.8 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H); [M+H]=355.25.

Example 335.[1-({5-[3-(Dimethylamino)phenyl]-6-ethoxypyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.74(d, J=2.3 Hz, 1H), 7.34-7.23 (m, 1H), 7.09 (br s, 1H), 7.00-6.85 (m,2H), 5.35 (s, 2H), 4.37 (s, 2H), 4.33 (q, J=7.0 Hz, 2H), 2.96 (s, 7H),1.27 (t, J=7.0 Hz, 3H); [M+H]=354.25.

Example 336.(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.81(d, J=2.3 Hz, 1H), 7.59-7.56 (m, 1H), 7.51-7.39 (m, 3H), 5.35 (s, 2H),5.15 (t, J=6.1 Hz, 1H), 4.36 (d, J=5.9 Hz, 2H), 3.87 (s, 3H);[M+H]=331.77.

Example 337.(1-{[5-(3-Chloro-4-fluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.82(d, J=2.3 Hz, 1H), 7.77 (dd, J=2.2, 7.2 Hz, 1H), 7.60-7.54 (m, 1H),7.51-7.44 (m, 1H), 5.33 (s, 2H), 5.15 (t, J=6.1 Hz, 1H), 4.39-4.30 (m,5H), 1.32-1.21 (m, 4H); [M+H]=363.25.

Example 338.(1-{[5-(3,5-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.22 (d, J=2.26 Hz, 1H), 7.89(d, J=2.26 Hz, 1H), 7.33 (dd, J=8.97, 2.20 Hz, 2H), 7.26 (d, J=2.26 Hz,1H), 5.35 (s, 2H), 5.18 (t, J=6.02 Hz, 1H), 4.32-4.45 (m, 4H), 1.30 (t,J=7.03 Hz, 3H); [M+H]=347.3.

Example 339.[1-({6-Ethoxy-5-[2-(trifluoromethyl)pyridin-4-yl]pyridin-3-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.74 (d, J=5.48 Hz, 1H), 8.54 (s, 1H), 8.30(d, J=2.35 Hz, 1H), 8.10 (d, J=1.17 Hz, 1H), 7.98 (d, J=2.35 Hz, 1H),7.88 (dd, J=5.09, 1.57 Hz, 1H), 5.43 (s, 2H), 4.59 (s, 2H), 4.47 (q,J=7.04 Hz, 2H), 1.37 (t, J=7.04 Hz, 3H); [M+H]=380.3.

Example 340.(1-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.19 (d, J=2.38 Hz, 1H), 7.82(d, J=2.26 Hz, 1H), 7.61-7.69 (m, 1H), 7.39-7.56 (m, 2H), 5.35 (s, 2H),5.18 (t, J=6.02 Hz, 1H), 4.31-4.42 (m, 4H), 1.29 (t, J=7.03 Hz, 3H);[M+H]=347.3.

Example 341.(1-{[6-Ethoxy-5-(3-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.20 (d, J=2.26 Hz, 1H), 7.83(d, J=2.38 Hz, 1H), 7.45-7.53 (m, 1H), 7.37-7.44 (m, 2H), 7.17-7.25 (m,1H), 5.36 (s, 2H), 5.18 (t, J=6.02 Hz, 1H), 4.30-4.45 (m, 4H), 1.29 (t,J=7.03 Hz, 3H); [M+H]=329.4.

Example 342.(1-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.17 (d, J=2.26 Hz, 1H), 7.76(d, J=2.26 Hz, 1H), 7.53-7.66 (m, 2H), 7.22-7.32 (m, 2H), 5.35 (s, 2H),5.18 (t, J=6.02 Hz, 1H), 4.30-4.43 (m, 4H), 1.28 (t, J=7.03 Hz, 3H);[M+H]=329.4.

Example 343.(1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.03-8.00 (m, 1H), 7.57-7.53 (m, 1H),7.25-7.20 (m, 1H), 7.14-6.99 (m, 3H), 5.18-5.13 (m, 2H), 4.48-4.43 (m,2H), 3.94 (s, 3H), 3.88 (s, 3H), 2.37 (s, 3H); [M+H]=358.

Example 344.(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.03-7.99 (m, 1H), 7.55-7.48 (m, 3H), 7.12 (t,J=8.8 Hz, 2H), 7.01 (s, 1H), 5.13 (s, 2H), 4.44 (d, J=0.8 Hz, 2H), 3.93(s, 3H), 2.35 (s, 3H); [M+H]=328.

Example 345.(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.3 Hz,1H), 7.51-7.44 (m, 1H), 7.30 (dd, J=1.6, 6.7 Hz, 2H), 7.02 (s, 1H),5.16-5.12 (m, 2H), 4.44 (s, 2H), 3.95 (s, 3H), 2.36 (s, 3H); [M+H]=346.

Example 346.(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=2.3 Hz, 1H), 7.57-7.51 (m, 2H),7.44-7.32 (m, 3H), 7.01 (s, 1H), 5.14 (s, 2H), 4.45 (d, J=0.8 Hz, 2H),3.94 (s, 3H), 2.36 (s, 3H); [M+H]=344.

Examples 347-349 were prepared in a manner analogous to Intermediate 21,with the appropriate starting material and reagent substitutions.

Example 347.4-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}pyridine-2-carbonitrile

¹H NMR (400 MHz, DMSO-d 6) δ 8.69-8.83 (m, 1H), 8.26 (dd, J=1.57, 0.78Hz, 1H), 8.08-8.24 (m, 3H), 7.92-8.03 (m, 1H), 7.90 (d, J=2.35 Hz, 1H),6.44 (s, 2H), 3.89 (s, 3H), 3.73 (s, 2H); [M+H]=319.37.

Example 348.2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.74-8.86 (m, 2H), 8.17 (d, J=2.35 Hz, 1H),7.80-7.91 (m, 1H), 7.65 (t, J=1.57 Hz, 1H), 7.30-7.60 (m, 3H), 6.13-6.54(m, 1H), 4.49-4.71 (m, 2H), 4.34 (s, 1H), 4.01 (s, 2H), 3.22-3.32 (m,1H); [M+H]=401.38.

Example 349.5-{[5-(2-Ethoxypyridin-4-yl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.07 (m, 4H), 7.75 (d, J=2.3 Hz, 1H),7.13 (dd, J=1.6, 5.5 Hz, 1H), 6.88 (s, 1H), 6.44 (br. s, 2H), 4.31 (q,J=7.0 Hz, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 1.31 (t, J=7.0 Hz, 3H);[M+H]=338.21.

Examples 350-362 were prepared in a manner analogous to Intermediate 24,with the appropriate starting material and reagent substitutions.

Example 350.5-{[6-Ethoxy-5-(4-fluorophenyl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) 8.3 s, 2H), 8.06 (d, J=2.3 Hz, 1H), 7.64 (d,J=2.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.28-7.19 (m, 2H), 4.31 (q, J=7.0 Hz,2H), 3.77 (s, 2H), 1.25 (t, J=7.0 Hz, 3H); [M+H]=325.25.

Example 351.5-{[5-(4-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 2H), 8.07 (d, J=2.3 Hz, 1H), 7.66(d, J=2.3 Hz, 1H), 7.60-7.54 (m, 3H), 7.51-7.43 (m, 3H), 4.31 (q, J=7.0Hz, 2H), 3.77 (s, 2H), 1.25 (t, J=7.0 Hz, 4H); [M+H]=341.25.

Example 352.5-{[6-Ethoxy-5-(4-fluoro-3-methylphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 2H), 8.04 (d, J=2.3 Hz, 1H), 7.62(d, J=2.3 Hz, 1H), 7.47-7.34 (m, 3H), 7.20-7.12 (m, 2H), 4.31 (q, J=7.0Hz, 2H), 3.75 (s, 2H), 2.25 (d, J=2.0 Hz, 3H), 1.29-1.20 (m, 3H);[M+H]=339.25.

Example 353.5-{[5-(3,4-Difluorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.08 (d, J=2.3 Hz, 1H), 7.70(d, J=2.3 Hz, 1H), 7.64 (ddd, J=2.3, 8.0, 12.3 Hz, 1H), 7.52-7.38 (m,2H), 4.33 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 1.27 (t, J=7.0 Hz, 3H);[M+H]=343.25.

Example 354.5-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 2H), 8.08 (d, J=2.3 Hz, 1H), 7.67(d, J=2.3 Hz, 1H), 7.30-7.25 (m, 1H), 7.25-7.19 (m, 1H), 7.07 (ddd,J=2.2, 4.4, 8.3 Hz, 1H), 3.84 (s, 6H), 3.79 (s, 2H); [M+H]=341.25.

Example 355.5-{[5-(3-Ethoxy-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.36-8.30 (m, 2H), 8.09-8.04 (m, 1H), 7.65(d, J=2.3 Hz, 1H), 7.30-7.19 (m, 3H), 7.06 (ddd, J=2.3, 4.5, 8.4 Hz,1H), 4.11 (q, J=7.0 Hz, 2H), 3.86-3.82 (m, 3H), 3.77 (s, 2H), 1.38-1.29(m, 3H); [M+H]=355.15.

Example 356.3-{5-[(2-Aminopyrimidin-5-yl)methyl]-2-methoxypyridin-3-yl}benzonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.26 (m, 2H), 8.14 (d, J=2.3 Hz, 1H),7.99 (t, J=1.8 Hz, 1H), 7.89 (td, J=1.5, 7.6 Hz, 1H), 7.81 (td, J=1.3,8.0 Hz, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 3.86 (s,3H), 3.78 (s, 2H); [M+H]=318.25.

Example 357.5-{[5-(4-Fluoro-3-methylphenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.07 (d, J=2.3 Hz, 1H), 7.62(d, J=2.3 Hz, 1H), 7.44-7.31 (m, 3H), 7.16 (dd, J=8.4, 9.6 Hz, 1H), 3.83(s, 3H), 3.77 (s, 2H), 2.25 (d, J=1.6 Hz, 3H); [M+H]=325.15.

Example 358.2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.81-8.76 (m, 2H), 8.16 (d, J=2.3 Hz, 1H),7.76 (d, J=2.3 Hz, 1H), 7.63 (ddd, J=2.2, 7.9, 12.2 Hz, 1H), 7.47 (td,J=8.5, 10.9 Hz, 1H), 7.42-7.34 (m, 1H), 4.34 (s, 2H), 3.98 (s, 2H), 3.85(s, 3H); [M+H]=353.35.

Example 359.5-{[5-(3-Chloro-4-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 2H), 8.11 (d, J=2.3 Hz, 1H),7.77-7.68 (m, 2H), 7.55 (ddd, J=2.2, 4.9, 8.6 Hz, 1H), 7.51-7.43 (m,1H), 3.85 (s, 3H), 3.78 (s, 2H); [M+H]=345.25.

Example 360.5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.64(d, J=2.3 Hz, 1H), 7.59-7.52 (m, 2H), 7.28-7.19 (m, 2H), 3.85-3.83 (m,3H), 3.78 (s, 2H); [M+H]=311.36.

Example 361.5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 7.73(d, J=2.3 Hz, 1H), 7.67-7.58 (m, 2H), 7.45-7.39 (m, 1H), 3.86 (s, 3H),3.78 (s, 2H); [M+H]=345.21.

Example 362.5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 2H), 8.11 (d, J=2.3 Hz, 1H), 7.70(d, J=2.3 Hz, 1H), 7.62 (ddd, J=2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, J=8.5,10.9 Hz, 1H), 7.42-7.34 (m, 2H), 3.85 (s, 3H), 3.77 (s, 2H);[M+H]=329.39.

Examples 363-365 were prepared in a manner analogous to Example 280,with the appropriate starting material and reagent substitutions.

Example 363.2-(4-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide

¹H NMR (400 MHz, CD₃OD) δ 8.09 (d, J=2.0 Hz, 1H), 7.66 (d, J=2.3 Hz,1H), 7.62 (ddd, J=2.2, 7.9, 12.2 Hz, 1H), 7.47 (td, J=8.6, 11.0 Hz, 1H),7.42-7.34 (m, 2H), 7.23-7.13 (m, 5H), 6.82 (br s, 1H), 3.90 (s, 2H),3.86 (s, 3H), 3.30 (s, 2H); [M+H]=369.40.

Example 364.2-(4-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.3 Hz,1H), 7.56-7.49 (m, 2H), 7.38 (br s, 1H), 7.26-7.20 (m, 2H), 7.20-7.12(m, 4H), 6.80 (br s, 1H), 3.88 (s, 2H), 3.82 (s, 3H), 3.29 (s, 2H);[M+H]=351.25.

Example 365.2-(4-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}phenyl)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=2.3 Hz, 1H), 7.68 (d, J=2.3 Hz,1H), 7.65-7.57 (m, 2H), 7.42-7.34 (m, 2H), 7.22-7.11 (m, 4H), 6.80 (brs, 1H), 3.89 (s, 2H), 3.84 (s, 3H), 3.28 (s, 2H); [M+H]=385.26.

Examples 366-372 were prepared in a manner analogous to Example 281,with the appropriate starting material and reagent substitutions.

Example 366.2-(5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 2H), 8.17 (d, J=2.3 Hz, 1H), 7.80(d, J=2.3 Hz, 1H), 7.65-7.58 (m, 3H), 7.44-7.40 (m, 2H), 3.94 (s, 2H),3.85 (s, 4H), 3.66 (s, 3H); [M+H]=387.25.

Example 367.2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)-2-methylpropanamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 2H), 8.15 (d, J=2.3 Hz, 1H), 7.78(d, J=2.3 Hz, 1H), 7.61-7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.47-7.38 (m,2H), 6.82 (br s, 2H), 3.94 (s, 2H), 3.30 (s, 2H), 1.45 (s, 7H);[M+H]=397.40.

Example 368.2-(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.19-8.15 (m, 1H), 7.78 (d,J=2.3 Hz, 1H), 7.69-7.60 (m, 1H), 7.51-7.44 (m, 2H), 7.43-7.35 (m, 2H),6.97 (br s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.67 (s, 2H); [M+H]=371.40.

Example 369.2-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 2H), 8.16 (d, J=2.0 Hz, 1H), 7.76(d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.53-7.37 (m, 4H), 6.95 (br s, 1H),3.94 (s, 2H), 3.84 (s, 3H), 3.65 (s, 2H); [M+H]=369.35.

Example 370.2-(5-{[5-(3-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ=8.71 (s, 2H), 8.20 (d, J=2.3 Hz, 1H), 7.92(d, J=2.3 Hz, 1H), 7.68-7.59 (m, 1H), 7.57-7.38 (m, 4H), 6.96 (br s,1H), 4.99 (q, J=9.3 Hz, 2H), 3.98 (s, 2H), 3.66 (s, 2H); [M+H]=437.39.

Example 371.2-(5-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}pyrimidin-2-yl)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ=8.70 (s, 2H), 8.17 (d, J=2.3 Hz, 1H), 7.87(d, J=2.3 Hz, 1H), 7.65 (t, J=1.6 Hz, 1H), 7.60-7.51 (m, 1H), 7.51-7.35(m, 3H), 6.96 (br s, 1H), 6.35 (t, J=3.5 Hz, 1H), 4.58 (dt, J=3.5, 15.1Hz, 2H), 3.97 (s, 2H), 3.66 (s, 2H), 3.55 (s, 1H); [M+H]=419.39.

Example 372.2-(1-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)acetamide

¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.27-8.24 (m, 1H), 7.94-7.92 (m,1H), 7.62 (s, 1H), 7.58-7.55 (m, 1H), 7.46 (s, 3H), 5.46-5.44 (m, 2H),3.65 (s, 2H); [M+H]=394.

Examples 373-374 were prepared in a manner analogous to Example 13, withthe appropriate starting material and reagent substitutions.

Example 373.5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 2H), 8.18 (d, J=2.3 Hz, 1H), 8.10(br s, 1H), 7.78 (d, J=2.3 Hz, 1H), 7.71 (br s, 1H), 7.63 (ddd, J=2.2,7.9, 12.2 Hz, 1H), 7.47 (td, J=8.6, 10.7 Hz, 1H), 7.41-7.34 (m, 1H),4.05 (s, 2H), 3.86 (s, 3H); [M+H]=357.15.

Example 374.5-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 2H), 8.15 (d, J=2.3 Hz, 1H), 8.10(br s, 1H), 7.71 (d, J=2.3 Hz, 2H), 7.60-7.52 (m, 2H), 7.28-7.19 (m,2H), 4.05 (s, 2H), 3.84 (s, 3H); [M+H]=339.15.

Example 375.2-[(5-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol

The title compound was prepared in a manner analogous to Example 3, withthe appropriate starting material and reagent substitutions. ¹H NMR (400MHz, DMSO-d₆) δ 8.20 (s, 2H), 8.08 (d, J=2.3 Hz, 1H), 7.67 (d, J=2.3 Hz,1H), 7.62 (ddd, J=2.2, 7.9, 12.2 Hz, 1H), 7.52-7.42 (m, 1H), 7.41-7.33(m, 1H), 6.84 (t, J=5.9 Hz, 1H), 4.63-4.56 (m, 1H), 3.85 (s, 3H), 3.72(s, 2H), 3.45 (q, J=6.1 Hz, 2H), 3.29-3.23 (m, 2H); [M+H]=373.40.

Examples 376-378 were prepared in a manner analogous to Intermediate 55,with the appropriate starting material and reagent substitutions.

Example 376.(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J=1.6 Hz, 2H), 8.17-8.13 (m, 1H),7.78-7.72 (m, 1H), 7.61-7.57 (m, 1H), 7.52-7.40 (m, 3H), 5.57-5.48 (m,1H), 4.63-4.54 (m, 2H), 4.19-4.10 (m, 2H), 3.86 (s, 3H); [M+H]=342.20.

Example 377.2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-5-methylpyrazine

¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J=1.17 Hz, 1H), 8.43 (s, 1H), 8.08(d, J=2.35 Hz, 1H), 7.64 (d, J=2.35 Hz, 1H), 7.52 (t, J=1.57 Hz, 1H),7.39-7.43 (m, 1H), 7.36 (t, J=7.63 Hz, 1H), 7.32 (t, J=1.96 Hz, 1H),4.12 (s, 2H), 3.92 (s, 3H), 2.50 (s, 3H); [M+H]=326.29.

Example 378.6-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrdine-3-carbonitrile

¹H NMR (400 MHz, CDCl₃) δ 8.83 (dd, J=0.78, 1.96 Hz, 1H), 8.09 (d,J=2.35 Hz, 1H), 7.85-7.92 (m, 1H), 7.47-7.55 (m, 2H), 7.39-7.43 (m, 1H),7.28-7.37 (m, 3H), 4.19 (s, 2H), 3.95-3.98 (m, 3H); [M+H]=336.34.

Example 379.5-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrazin-2-amine

The title compound was prepared in a manner analogous to Example 287,employing tert-butyl(5-((5-(3-chloro-4-fluorophenyl)-6-methoxypyridin-3-yl)methyl)pyrazin-2-yl)carbamate(Intermediate 56). ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=2.35 Hz, 1H),7.95 (d, J=1.56 Hz, 1H), 7.91 (d, J=1.17 Hz, 1H), 7.49 (d, J=2.35 Hz,1H), 7.35-7.44 (m, 2H), 7.26 (dd, J=0.78, 1.96 Hz, 1H), 4.54 (br s, 2H),3.98 (s, 2H), 3.96 (s, 3H); [M+H]=345.35.

Examples 380-388 were prepared in a manner analogous to Intermediate 32,with the appropriate starting material and reagent substitutions.

Example 380.3-(3-Chlorophenyl)-2-methoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=2.35 Hz, 1H), 7.52 (d, J=2.35 Hz,1H), 7.47-7.50 (m, 1H), 7.31-7.38 (m, 3H), 5.47 (s, 2H), 3.97 (s, 3H),2.55 (s, 3H); [M+H]=313.36.

Example 381.(2-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=2.35 Hz, 1H), 7.65 (d, J=2.35 Hz,1H), 7.45-7.53 (m, 2H), 7.08-7.16 (m, 2H), 5.75 (s, 2H), 4.94 (s, 2H),3.98 (s, 3H).

Example 382.(1-{[5-(4-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J=2.35 Hz, 1H), 7.78 (d, J=2.35 Hz,1H), 7.50-7.57 (m, 2H), 7.09-7.17 (m, 2H), 5.72 (s, 2H), 4.95 (s, 2H),3.95 (s, 3H); [M+H]=316.08.

Example 383.(2-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=2.35 Hz, 1H), 7.65 (d, J=2.35 Hz,1H), 7.35-7.44 (m, 1H), 7.16-7.25 (m, 2H), 5.75 (s, 2H), 4.94 (s, 2H),3.99 (s, 3H); [M+H]=334.42.

Example 384.(1-{[5-(3,4-Difluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.35 Hz, 1H), 7.65 (d, J=2.35 Hz,1H), 7.34-7.43 (m, 1H), 7.15-7.23 (m, 2H), 5.65 (s, 2H), 4.99 (s, 2H),3.97 (s, 3H); [M+H]=334.42.

Example 385.(2-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=2.35 Hz, 1H), 7.67 (d, J=2.35 Hz,1H), 7.44 (t, J=8.02 Hz, 1H), 7.37 (dd, J=1.96, 10.17 Hz, 1H), 7.22-7.26(m, 1H), 5.75 (s, 2H), 4.94 (s, 2H), 3.99 (s, 3H); [M+H]=350.08.

Example 386.(1-{[5-(4-Chloro-3-fluorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.28 (d, J=2.35 Hz, 1H), 7.85 (d, J=2.35 Hz,1H), 7.44-7.54 (m, 2H), 7.30-7.37 (m, 1H), 5.73 (s, 2H), 4.95 (s, 2H),3.97 (s, 3H); [M+H]=350.08.

Example 387.(1-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CD₃OD) δ 8.25-8.28 (m, 1H), 7.80 (d, J=2.35 Hz, 1H),7.53 (t, J=1.76 Hz, 1H), 7.40-7.44 (m, 1H), 7.32-7.40 (m, 2H), 5.72 (s,2H), 4.95 (s, 2H), 3.95 (s, 3H); [M+H]=332.03.

Example 388.(2-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-2H-1,2,3,4-tetrazol-5-yl)methanol

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=2.35 Hz, 1H), 7.67 (d, J=2.35 Hz,1H), 7.52 (q, J=1.57 Hz, 1H), 7.33-7.42 (m, 3H), 5.75 (s, 2H), 4.94 (s,2H), 3.98 (s, 3H); [M+H]=332.03.

Examples 389-391 were prepared in a manner analogous to Example 292,with the appropriate starting material and reagent substitutions.

Example 389.1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)pyrrolidin-3-ol

¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 2H), 8.03 (d, J=2.35 Hz, 1H), 7.55(d, J=2.35 Hz, 1H), 7.53 (t, J=1.76 Hz, 1H), 7.40-7.44 (m, 1H), 7.37 (t,J=7.63 Hz, 1H), 7.31-7.35 (m, 1H), 4.46-4.53 (m, 1H), 3.93 (s, 3H), 3.83(s, 2H), 3.59-3.68 (m, 3H), 3.52-3.57 (m, 1H), 1.97-2.17 (m, 2H).

Example 390.1-(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)azetidin-3-ol

¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 2H), 8.03 (d, J=2.35 Hz, 1H), 7.56(d, J=2.35 Hz, 1H), 7.53 (t, J=1.57 Hz, 1H), 7.41-7.44 (m, 1H), 7.37 (t,J=7.63 Hz, 1H), 7.31-7.35 (m, 1H), 4.61-4.69 (m, 1H), 4.27-4.36 (m, 2H),3.93 (s, 3H), 3.86-3.90 (m, 2H), 3.84 (s, 2H); [M+H]=383.4.

Example 391.2-[(5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-yl)amino]ethan-1-ol

¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 2H), 8.03 (d, J=2.35 Hz, 1H), 7.56(d, J=2.74 Hz, 1H), 7.53 (t, J=1.57 Hz, 1H), 7.41-7.45 (m, 1H), 7.38 (t,J=7.63 Hz, 1H), 7.31-7.35 (m, 1H), 3.93 (s, 3H), 3.82 (s, 2H), 3.65-3.72(m, 2H), 3.43-3.51 (m, 2H); [M+H]=371.39.

Examples 392-402 were prepared in a manner analogous to Intermediate 21,with the appropriate starting material and reagent substitutions.

Example 392.2-Ethoxy-3-(4-fluorophenyl)-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=1.96 Hz, 1H), 7.63 (d, J=1.96 Hz,1H), 7.47-7.56 (m, 2H), 7.06-7.15 (m, 2H), 5.68 (s, 2H), 4.43 (q, J=7.04Hz, 2H), 2.52 (s, 3H), 1.37 (t, J=6.85 Hz, 3H); [M+H]=314.42.

Example 393.3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=2.35 Hz, 1H), 7.63 (d, J=2.35 Hz,1H), 7.42 (ddd, J=2.15, 7.53, 11.44 Hz, 1H), 7.17-7.26 (m, 2H), 5.68 (s,2H), 4.44 (q, J=7.04 Hz, 2H), 2.53 (s, 3H), 1.38 (t, J=7.04 Hz, 3H);[M+H]=332.4.

Example 394.3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-2H-1,2,3,4-tetrazol-2-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=2.35 Hz, 1H), 8.20-8.24 (m, 1H),7.71 (d, J=2.35 Hz, 1H), 7.50 (t, J=73.20 Hz, 1H), 7.27-7.29 (m, 1H),7.11 (dd, J=0.78, 1.57 Hz, 1H), 5.69 (s, 2H), 4.45 (q, J=7.04 Hz, 2H),2.52 (s, 3H), 1.38 (t, J=7.04 Hz, 3H); [M+H]=363.41.

Example 395.3-(3,4-Difluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=2.35 Hz, 1H), 7.52 (d, J=2.35 Hz,1H), 7.34-7.45 (m, 1H), 7.15-7.23 (m, 2H), 5.46 (s, 2H), 4.43 (q, J=7.04Hz, 2H), 2.56 (s, 3H), 1.37 (t, J=7.04 Hz, 3H); [M+H]=332.4.

Example 396.3-[2-(Difluoromethoxy)pyridin-4-yl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=4.70 Hz, 1H), 8.19 (d, J=2.35 Hz,1H), 7.61 (d, J=2.35 Hz, 1H), 7.50 (t, J=73.60 Hz, 1H), 7.25 (dd,J=1.37, 5.28 Hz, 1H), 7.09 (d, J=0.78 Hz, 1H), 5.47 (s, 2H), 4.46 (q,J=7.04 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J=7.24 Hz, 3H); [M+H]=363.41.

Example 397.3-(4-Chloro-3-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=2.74 Hz, 1H), 7.53 (d, J=2.74 Hz,1H), 7.41-7.46 (m, 1H), 7.37 (dd, J=2.15, 10.37 Hz, 1H), 7.19-7.24 (m,1H), 5.46 (s, 2H), 4.44 (q, J=7.04 Hz, 2H), 2.56 (s, 3H), 1.35-1.42 (m,3H); [M+H]=348.36.

Example 398.3-(3-Chloro-4-fluorophenyl)-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=2.35 Hz, 1H), 7.57 (dd, J=2.35,7.04 Hz, 1H), 7.51 (d, J=2.35 Hz, 1H), 7.37 (ddd, J=2.15, 4.50, 8.61 Hz,1H), 7.18 (t, J=8.61 Hz, 1H), 5.46 (s, 2H), 4.43 (q, J=7.04 Hz, 2H),2.56 (s, 3H), 1.37 (t, J=7.04 Hz, 3H); [M+H]=348.36.

Example 399.3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=2.3 Hz, 1H), 7.55 (d, J=2.3 Hz,1H), 7.44-7.39 (m, 1H), 7.37 (s, 1H), 7.34-7.30 (m, 1H), 7.13 (dd,J=2.2, 8.0 Hz, 1H), 6.55 (t, J=73.6 Hz, 1H), 5.47 (s, 2H), 4.43 (q,J=7.0 Hz, 2H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz, 3H).

Example 400.2-Ethoxy-3-(2-ethoxypyridin-4-yl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.58 (brs, 1H), 7.03 (d, J=5.1 Hz, 1H), 6.87 (s, 1H), 5.46 (s, 2H), 4.49-4.36(m, 4H), 2.59-2.54 (m, 3H), 1.46-1.36 (m, 6H).

Example 401.2-Ethoxy-3-(3-ethoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=2.3 Hz, 1H), 7.53 (d, J=2.3 Hz,1H), 7.32 (t, J=8.0 Hz, 1H), 7.08-7.04 (m, 2H), 6.93-6.89 (m, 1H), 5.46(s, 2H), 4.43 (q, J=7.0 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 2.55 (s, 3H),1.44 (t, J=6.8 Hz, 3H), 1.38 (t, J=7.0 Hz, 3H).

Example 402.2-Ethoxy-3-(3-fluoro-5-methoxyphenyl)-5-[(5-methyl-1H-1,2,3,4-tetrazol-1-yl)methyl]pyridine

¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=2.3 Hz, 1H), 7.54 (d, J=2.3 Hz,1H), 6.88-6.80 (m, 2H), 6.63 (td, J=2.3, 10.6 Hz, 1H), 5.46 (s, 2H),4.44 (q, J=7.0 Hz, 2H), 3.83 (s, 3H), 2.56 (s, 3H), 1.38 (t, J=7.0 Hz,3H).

Example 403.3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine

The title compound was prepared in a manner analogous to Example 297,with the appropriate starting material and reagent substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.10 (s, 3H), 7.42 (d, J=1.2 Hz, 3H), 6.77-6.48 (m,1H), 5.31 (s, 2H), 4.51 (d, J=7.0 Hz, 2H), 2.48 (s, 3H), 1.44 (s, 3H);[M+H]=379.

Examples 404-405 were prepared in a manner analogous to Example 299,with the appropriate starting material and reagent substitutions.

Example 404.(5-{[6-(2,2-Difluoroethoxy)-5-(2-ethoxypyridin-4-yl)pyridin-3-yl]methyl}-3-fluoropyridin-2-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (t, J=1.76 Hz, 1H), 8.12-8.26 (m, 2H),7.92 (d, J=2.35 Hz, 1H), 7.65 (dd, J=10.76, 1.76 Hz, 1H), 7.17 (dd,J=5.48, 1.57 Hz, 1H), 6.99 (dd, J=1.57, 0.78 Hz, 1H), 5.19 (t, J=5.87Hz, 1H), 4.45-4.66 (m, 4H), 4.31 (q, J=7.04 Hz, 2H), 4.01 (s, 2H), 1.31(t, J=7.04 Hz, 3H); [M+H]=420.5.

Example 405.[5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-ethoxypyridin-3-yl}methyl)-3-fluoropyridin-2-yl]methanol

¹H NMR (400 MHz, CD₃OD) δ 8.34-8.29 (m, 1H), 8.23-8.19 (m, 1H),8.13-8.10 (m, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.56 (s, 1H), 7.53-7.48 (m,1H), 7.43-7.39 (m, 1H), 7.21-7.18 (m, 1H), 4.75-4.68 (m, 2H), 4.46-4.38(m, 2H), 4.08-4.03 (m, 2H), 1.39-1.32 (m, 3H); [M+H]=406.

Example 406.(1-{[5-(3-Chlorophenyl)-6-(2,2-difluoroethoxy)pyridin-3-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol

The title compound was prepared in a manner analogous to Intermediate35, with the appropriate starting material and reagent substitutions. ¹HNMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=2.35 Hz, 1H), 7.80 (d, J=1.96 Hz,1H), 7.64 (dt, J=2.45, 0.93 Hz, 1H), 7.37-7.59 (m, 3H), 6.97 (s, 1H),6.36 (t, J=3.52 Hz, 1H), 5.08 (s, 2H), 4.52-4.74 (m, 3H), 4.22 (dd,J=5.48, 0.78 Hz, 2H), 2.27 (s, 3H); [M+H]=394.41.

Example 407.1-{[5-(4-Fluoro-3-methoxyphenyl)-6-methoxypyridin-3-yl]methyl}-1H-1,2,4-triazol-3-amine

The title compound was prepared in a manner analogous to Intermediate10, employing Intermediate 36. ¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 2H),7.68 (d, J=2.3 Hz, 1H), 7.27-7.22 (m, 1H), 7.10 (d, J=11.0 Hz, 2H),5.20-5.16 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H); [M+H]=330.

PHARMACOLOGICAL EXAMPLES

The present disclosure will be further illustrated by the followingpharmacological examples. These examples are understood to be exemplaryonly and are not intended to limit the scope of the invention disclosedherein.

Enzymatic Assay

An IMAP TR-FRET based PDE assay was developed using the PDE4D3 isoform.IMAP technology is based on high-affinity binding of phosphate byimmobilized metal (MIII) coordination complexes on nanoparticles. TheIMAP “binding reagent” recognizes phosphate groups on AMP or GMPgenerated from cAMP or cGMP in a PDE reaction. The cyclic nucleotidesthat carry a phosphodiester bond and not a free phosphate are notrecognized by the binding reagent. The time resolved fluorescenceresonance energy transfer (TR-FRET) is afforded by a Terbium (Tb)-Donorprebound to the nanoparticles. FRET can occur when fluorescent-labeledAMP or GMP product of a PDE reaction binds comes into close proximity ofthe Tb-Donor complex. Due to the long lifetime of Tb fluorescence,detection can be run in time-resolved mode to eliminate interferencefrom autofluorescent compounds.

The IMAP TR-FRET PDE4D3 FAM-cAMP assay was performed in 1536-well whiteplates 15 pg per well GST-tagged PDE4D3 was dispensed in 2.5 μL IMAPassay buffer consisting of 10 mM Tris pH 7.2, 10 mM MgCl₂, 1 mM DTT,0.1% fatty acid free BSA and 0.01% Tween-20. 30 nL of compound was thenadded from 1 mM stock in DMSO using the Kalypsys 1536 10 nL pintool.Plates were incubated for 5 min at RT before dispensing 1.5 μL of 533 nMFAM-cAMP for a final concentration of 200 nM. Plates were incubated 30min at RT after a brief centrifugation. The assay was terminated byadding 5 μL IMAP binding reagent Tb complex to each well, preparedaccording to manufacturer's recommendations. Plates were incubated anadditional 90 minutes at RT and read on a Viewlux plate reader.Compounds were solvated at 10 mM in DMSO and tested in 11-pointdose-response in the PDE4D3 assay.

Pharmacological Example 1 PDE4 Inhibition

Representative compounds of the invention were evaluated in the PDE4enzymatic assay. Typically, the compounds of the invention show PDE4inhibitory properties at a concentration of 0.1 to 10 μM, typically at5-100%.

As depicted in the following Table, these inhibitory properties weremirrored by pEC₅₀ values ranging from less than 5 (10⁻⁵ M or 10 μM) togreater than 7 (10⁻⁷ M or 0.1 μM).

PD4d3 pEC₅₀ Example Numbers >7 1, 13, 25, 27, 28, 29, 30, 32, 33, 36,38, 40, 46, 47, 48, 55, 56, 58, 65, 66, 68, 69, 71, 72, 73, 76, 78, 79,80, 82, 84, 87, 89, 92, 93, 95, 100, 103, 104, 105, 106, 110, 119, 122,123, 124, 125, 126, 131, 134, 142, 143, 144, 147, 150, 152, 154, 161,164, 167, 172, 173, 182, 184, 200, 201, 202, 203, 204, 205, 216, 225,228, 229, 231, 244, 250, 253, 257, 258, 259, 260, 261, 269, 271, 272,278, 279, 280, 281, 287, 288, 290, 291, 293, 294, 296, 298, 299, 301,303, 306, 309, 312, 325, 326, 327, 336, 337, 340, 348, 349, 350, 352,353, 358, 359, 360, 362, 363, 364, 365, 368, 369, 371, 372, 375, 376,377, 380, 391, 392, 393, 394, 395, 396, 398, 399, 404, 405, 406,Intermediate 49, 6-7 2, 5, 7, 12, 14, 20, 21, 24, 26, 34, 37, 41, 43,44, 45, 49, 51, 53, 57, 59, 60, 64, 67, 74, 75, 81, 83, 85, 86, 88, 90,91, 94, 96, 97, 102, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117,118, 120, 121, 128, 129, 130, 132, 136, 137, 139, 141, 145, 146, 149,151, 153, 156, 158, 159, 160, 162, 163, 165, 166, 169, 170, 175, 177,178, 179, 187, 188, 190, 199, 206, 207, 210, 211, 212, 213, 215, 217,218, 219, 220, 221, 222, 223, 226, 230, 232, 233, 237, 238, 242, 243,247, 248, 249, 251, 252, 256, 262, 263, 264, 265, 266, 268, 273, 274,275, 282, 283, 285, 289, 297, 300, 304, 305, 308, 310, 311, 313, 314,315, 316, 317, 319, 321, 322, 324, 328, 330, 331, 333, 334, 338, 341,342, 344, 345, 346, 347, 351, 354, 355, 356, 357, 361, 366, 367, 370,373, 374, 378, 379, 381, 383, 385, 388, 389, 390, 397, 400, 401, 402,403, Intermediate 50, 5-6 3, 8, 15, 16, 17, 18, 19, 23, 31, 35, 39, 42,50, 52, 54, 61, 62, 63, 70, 77, 98, 99, 101, 127, 133, 135, 138, 148,155, 157, 168, 171, 176, 180, 181, 183, 185, 186, 189, 191, 192, 193,194, 195, 196, 197, 198, 208, 209, 214, 224, 227, 234, 236, 239, 240,241, 245, 254, 255, 270, 276, 284, 292, 295, 302, 307, 318, 323, 329,332, 335, 339, 343, 382, 384, 386, 387, 407, <5 4, 6, 9, 10, 11, 22,140, 174, 235, 246, 267, 277, 286, 320.

Biological Examples

The present disclosure will be further illustrated by the followingbiological examples. These examples are understood to be exemplary onlyand are not intended to limit the scope of the invention disclosedherein.

Behavioral Assays

Numerous behavioral assays are available to assess the ability of acandidate compound to enhance memory formation, including contextualconditioning (e.g., fear conditioning), temporal conditioning (e.g.,trace conditioning), and object recognition. Other non-limiting examplesof appropriate assays to assess memory include those that incorporate orrelate to multiple training sessions, spaced training sessions,contextual fear training with single or multiple trials, trace fearconditioning with single or multiple trials, contextual memorygenerally, temporal memory, spatial memory, episodic memory, passiveavoidance memory, active avoidance memory, food preference memory,conditioned taste avoidance, and social recognition memory.

The behavioral assays can also be used in accordance with the presentinvention, as will be understood by those of ordinary skill in the art.These assays can be directed towards the evaluation of, withoutlimitation, hippocampus-, cortex, and/or amygdala-dependent memoryformation or cognitive performance.

Biological Example 1 Effect of PDE4 Inhibitors on Contextual MemoryRationale

Contextual fear conditioning is a form of associative learning in whichanimals learn to recognize a training environment (conditioned stimulus,CS) that has been previously paired with an aversive stimulus such asfoot shock (unconditioned stimulus, US). When exposed to the samecontext at a later time, conditioned animals show a variety ofconditional fear responses, including freezing behavior. The percent oftime during the test that the animal exhibits such freezing provides aquantitative measure of the contextual associative memory (e.g.,Fanselow, Behav. Neurosci. 1984, 98, 269-277; Fanselow, Behav. Neurosci.1984, 98, 79-95; and Phillips and LeDoux, Behav. Neurosci. 1992, 106,274-285).

Contextual conditioning has been extensively used to investigate theneural substrates mediating fear-motivated learning (e.g., Phillips andLeDoux, Behav. Neurosci. 1992, 106, 274-285; Kim et al., Behav.Neurosci. 1993, 107, 1093-1098; and Bourtchouladze et al., Learn. Mem.1998, S, 365-374). Studies in mice and rats provided evidence forfunctional interaction between hippocampal and nonhippocampal systemsduring contextual conditioning training (e.g., Maren et al., Behav.Brain Res. 1997, 88, 261-274; Maren et al., Neurobiol. Learn. Mem. 1997,67, 142-149; and Frankland et al., Behav. Neurosci. 1998, 112, 863-874).Specifically, post-training lesions of the hippocampus (but notpre-training lesions) greatly reduced contextual fear, implying that: 1)the hippocampus is essential for contextual memory but not forcontextual learning per se and 2) in the absence of the hippocampusduring training, non-hippocampal systems can support contextualconditioning.

Contextual conditioning has been extensively used to study the impact ofvarious mutations on hippocampus-dependent learning, as well as strainand genetic background differences in mice (e.g., Bourtchouladze et al.,Cell 1994, 79, 59-68; Bourtchouladze et al., Learn Mem. 1998, S,365-374; Kogan et al., Current Biology 1997, 7, 1-11; Silva et al.,Current Biology 1996, 6, 1509-1518; Abel et al., Cell 1997, 88, 615-626;Giese et al., Science 1998, 279, 870-873; Logue et al., Neuroscience1997, 80, 1075-1086; Chen et al., Behav. Neurosci. 1996, 110, 1177-1180;and Nguyen et al., Learn Mem. 2000, 7, 170-179).

Because robust learning can be triggered with a few minutes trainingsession, contextual conditioning has been especially useful to study thebiology of temporally distinct processes of short- and long-term memory(e.g., Kim et al., Behav. Neurosci. 1993, 107, 1093-1098; Bourtchouladzeet al., Cell 1994, 79, 59-68; Abel et al., Cell 1997, 88, 615-626; Logueet al., Behav. Neurosci. 1997, 111, 104-113; Bourtchouladze et al.,Learn. Mem. 1998, S, 365-374; and Nguyen et al., Learn. Mem. 2000, 7,170-179). As such, contextual conditioning provides an excellent modelto evaluate the effects of novel drug compounds on hippocampal-dependentmemory formation.

Procedures

Previous investigations have established that training with 1× or2×CS-US pairings induces sub-maximal (weak) memory in wild-type mice(e.g., U.S.2009/0053140; Tully et al., Nat. Rev. Drug Discov. 2003, 2,267-77; and Bourtchouladze et al. Learn. Mem. 1998, 5, 365-374).Accordingly, contextual conditioning in this study was performed asdescribed by Bourtchouladze et al., Cell 1994, 79, 59-68.

Young-adult (10-12 weeks old) C57BL/6 male mice and Sprague Dawley malerats were used. Mice and rats were group-housed in standard laboratoryand maintained on a 12:12 light-dark cycle. The experiments were alwaysconducted during the light phase of the cycle. With the exception oftesting times, the mice had ad libidum access to food and water. Toassess contextual memory, a modified contextual fear conditioning taskoriginally developed for evaluation of memory in CREB knock-out mice wasused (Bourtchouladze et al., 1994). Training sessions are comprised of abaseline period in the conditioning chamber (Med Associates, Inc.)followed by presentation of unconditioned stimuli (1-5 footshocks eachat 0.2-1.0 mA for 2-sec) spaced at 60-sec intervals. Thirty secondsfollowing the last shock, the animal is returned to the home cage. Oneto 7 days later, the animals are returned to the chamber and freezingbehavior is scored. Freezing (complete immobility except respiration) isscored by Video Freeze software (Med Associates, Inc.) over an 8 minutetest period. Treatment with cognition enhancers are expected tosignificantly increase freezing when compared with controls.

All experiments were designed and performed in a counterbalancedfashion. In each experiment, the experimenter was unaware (blind) to thetreatment of the subjects during training and testing. Training and testsessions were recorded as digital video files. Data were analyzed byone-way ANOVA with appropriate post-hoc tests using GraphPad Prismsoftware package.

Results

Exemplary compounds were found to enhance contextual memory in the fearconditioning assay. Significant enhancing effects are seen at severalconcentrations, including 0.01 mg/kg, 0.03 mg/kg, and 1.0 mg/kg.

Biological Example 2 Effect of PDE4 Inhibitors on Novel ObjectRecognition Rationale

Novel Object Recognition (NOR) is an assay of recognition learning andmemory retrieval, and it takes advantage of the spontaneous preferenceof rodents to investigate a novel object compared with a familiar one.It is an ethologically relevant task, which in contrast to fearconditioning, does not result from negative reinforcement (footshock)(e.g., Ennaceur and Delacour, Behav. Brain Res. 1988, 31, 47-59).

The NOR test has been employed extensively to assess the potentialcognitive-enhancing properties of novel compounds derived fromhigh-throughput screening. Object recognition the task relies on thenatural curiosity of rodents to explore novel objects in theirenvironments more than familiar ones. Obviously, for an object to be“familiar,” the animal must have attended to it before and rememberedthat experience. Hence, animals with better memory will attend andexplore a new object more than an object familiar to them. Duringtesting, the animal is presented with the training object and a second,novel one. Memory of the training object renders it familiar to theanimal, and it then spends more time exploring the new novel objectrather than the familiar one (Bourtchouladze et. al., Proc. Natl. AcadSci. USA 2003, 100, 10518-10522).

Neuroimaging, pharmacological, and lesion studies have demonstrated thatthe hippocampus and adjacent perirhinal cortex are critical for objectrecognition memory in rodents, monkeys, and humans (e.g., Mitchell,Behav. Brain Res. 1998, 97, 107-113; Teng et al., J. Neurosci. 2000, 20,3853-3863; Mumby, Brain Res. 2001, 127, 159-181; Eichenbaum et al.,Annu. Rev. Neurosci. 2007, 30, 127-152; Squire et al., Nat. Rev.Neurosci. 2007, 8, 872-883; and Vann and Alabasser, Curr. Opin.Neurobiol. 2011, 21, 440-445). Hence, object recognition provides anexcellent behavioral model to evaluate drug-compound effects oncognitive tasks associated with function of the hippocampus and cortex.

Procedures

Object recognition was tested in young adult mice and rats using thefollowing protocol. Animals are briefly handled by the experimenter 2-5days prior to training. Each compound was administered between 15minutes and 24-hours prior to, or following, training. Habituationsessions (duration 1-20 min, over 1-3 days) were conducted tofamiliarize the animal to the arena. During training trials (duration of1-20 min) the animals were allowed to explore two identical objects. Atest trial (duration of 1-20 min) was then performed 1-96 hrs later.

For novel object recognition, one object is replaced with one that isnovel. All combinations and locations of objects are used in a balancedmanner to reduce potential biases attributable to preference forparticular locations or objects. Training and test trials are recordedand scored by video-tracking software (e.g. Noldus Ethovision). Ananimal is scored as exploring an object when its head was orientedtoward the object within a distance of 1 cm (rat)/2 cm (mouse) or whenthe nose is touching the object. Turning around, climbing, or sitting onan object was not considered as exploration. If the animal generates along-term memory for the familiar object, it will spend significantlymore time exploring the novel object compared to the familiar objectduring the retention test (Cognitive enhancers are therefore expected tofacilitate this discrimination between the familiar and novel object).

A discrimination index was calculated as previously described(Bourtchouladze et al., Proc. Nad. Acad. Sci. USA 2003, 100,10518-10522). In each experiment, the experimenter was unaware (blind)to the treatment of the subjects during training and testing. Data wereanalyzed by one-way ANOVA with appropriate post-hoc tests using GraphPadPrism software package.

Results

Exemplary compounds of Formula (I) were found to significantly enhance24 hour memory. Significant effects were seen at several concentrations,including 1.0 mg/kg and 3 mg/kg.

The specification, including the examples, is intended to be exemplaryonly, and it will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention as definedby the appended claims.

Furthermore, while certain details in the present disclosure areprovided to convey a thorough understanding of the invention as definedby the appended claims, it will be apparent to those skilled in the artthat certain embodiments may be practiced without these details.Moreover, in certain instances, well-known methods, procedures, or otherspecific details have not been described to avoid unnecessarilyobscuring aspects of the invention defined by the appended claims.

1.-20. (canceled)
 21. A compound selected from the group consisting of:5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide;(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;and pharmaceutically acceptable salts thereof.
 22. The compound of claim21, which is5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 23. The compound of claim21, which is4-{[5-(3-chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 24. The compound of claim21, which is5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridine-3-carboxamide;or a pharmaceutically acceptable salt thereof.
 25. The compound of claim21, which is(1-{[6-(Difluoromethoxy)-5-(3-ethoxyphenyl)pyridin-3-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;or a pharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition comprising an effective amount of a compound, orpharmaceutically acceptable salt thereof, of claim 21; and apharmaceutically acceptable excipient.
 27. A method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by PDE4 enzymatic activity, comprising administeringto a subject in need of such treatment an effective amount of a compoundof claim 21, wherein the disorder is selected from one or more of thegroup selected from Alzheimer's Disease, Age Associated MemoryImpairment (AAMI), Age Associated Cognitive Decline, vascular dementia,delirium, Parkinson's disease, Huntington's disease, Pick's disease,mental retardation, cerebrovascular disease, an affective disorder,psychotic disorders, neurotic disorders, attention deficit disorder,subdural hematoma, normal-pressure hydrocephalus, brain tumor, stroke,cognitive impairment due to sleep deprivation, intellectual anddevelopmental disabilities; multiple sclerosis; inflammatory boweldisease; rheumatoid arthritis; COPD, asthma, allergic rhinitis,pulmonary artery hypertension; renal diseases; allergic skin diseasesand psoriasis.
 28. A method of treating a neurological disorder,comprising administering to a subject in need of such treatment aneffective amount of a compound of claim 21.